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Sauvage, Eric, Eveline Fonzé, Birgit Quinting, Moreno Galleni, Jean-Marie Frère, and Paulette Charlier. "Crystal Structure of the Mycobacterium fortuitum Class A β-Lactamase: Structural Basis for Broad Substrate Specificity." Antimicrobial Agents and Chemotherapy 50, no. 7 (July 2006): 2516–21. http://dx.doi.org/10.1128/aac.01226-05.
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ABSTRACT β-Lactamases are the main cause of bacterial resistance to penicillins and cephalosporins. Class A β-lactamases, the largest group of β-lactamases, have been found in many bacterial strains, including mycobacteria, for which no β-lactamase structure has been previously reported. The crystal structure of the class A β-lactamase from Mycobacterium fortuitum (MFO) has been solved at 2.13-Å resolution. The enzyme is a chromosomally encoded broad-spectrum β-lactamase with low specific activity on cefotaxime. Specific features of the active site of the class A β-lactamase from M. fortuitum are consistent with its specificity profile. Arg278 and Ser237 favor cephalosporinase activity and could explain its broad substrate activity. The MFO active site presents similarities with the CTX-M type extended-spectrum β-lactamases but lacks a specific feature of these enzymes, the VNYN motif (residues 103 to 106), which confers on CTX-M-type extended-spectrum β-lactamases a more efficient cefotaximase activity.
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Williams, J. D. "β-Lactamases and β-lactamase inhibitors." International Journal of Antimicrobial Agents 12 (August 1999): S3—S7. http://dx.doi.org/10.1016/s0924-8579(99)00085-0.
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Pradel, N., J. Delmas, L. F. Wu, C. L. Santini, and R. Bonnet. "Sec- and Tat-Dependent Translocation of β-Lactamases across the Escherichia coli Inner Membrane." Antimicrobial Agents and Chemotherapy 53, no. 1 (November 3, 2008): 242–48. http://dx.doi.org/10.1128/aac.00642-08.
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ABSTRACT β-Lactamases represent the major resistance mechanism of gram-negative bacteria against β-lactam antibiotics. The amino acid sequences of these proteins vary widely, but all are located in the periplasm of bacteria. In this study, we investigated the translocation mechanism of representative β-lactamases in an Escherichia coli model. N-terminal signal sequence analyses, antibiotic activity assay, and direct measurement of translocation of a green fluorescent protein (GFP) reporter fused to β-lactamases revealed that most were exported via the Sec pathway. However, the Stenotrophomonas maltophilia L2 β-lactamase was exported via the E. coli Tat translocase, while the S. maltophilia L1 β-lactamase was Sec dependent. These results show the possible Tat-dependent translocation of β-lactamases in the E. coli model system. In addition, the mutation of the cytoskeleton-encoding gene mreB, which may be involved in the spatial organization of penicillin-binding proteins, decreased the MIC of β-lactams for β-lactamase-producing E. coli. These findings provide new knowledge about β-lactamase translocation, a putative new target for addressing β-lactamase-mediated resistance.
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Thomson, Kenneth S., Christine C. Sanders, and Ellen Smith Moland. "Use of Microdilution Panels with and without β-Lactamase Inhibitors as a Phenotypic Test for β-Lactamase Production among Escherichia coli, Klebsiella spp.,Enterobacter spp., Citrobacter freundii, andSerratia marcescens." Antimicrobial Agents and Chemotherapy 43, no. 6 (June 1, 1999): 1393–400. http://dx.doi.org/10.1128/aac.43.6.1393.
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ABSTRACT Over the past decade, a number of new β-lactamases have appeared in clinical isolates of Enterobacteriaceaethat, unlike their predecessors, do not confer β-lactam resistance that is readily detected in routine antibiotic susceptibility tests. Because optimal methodologies are needed to detect these important new β-lactamases, a study was designed to evaluate the ability of a panel of various β-lactam antibiotics tested alone and in combination with β-lactamase inhibitors to discriminate between the production of extended-spectrum β-lactamases, AmpC β-lactamases, high levels of K1 β-lactamase, and other β-lactamases in 141 isolates of Escherichia coli,Klebsiella pneumoniae, Klebsiella oxytoca,Enterobacter cloacae, Enterobacter aerogenes,Citrobacter freundii, and Serratia marcescens possessing well-characterized β-lactamases. The microdilution panels studied contained aztreonam, cefpodoxime, ceftazidime, cefotaxime, and ceftriaxone, with and without 1, 2, and 4 μg of clavulanate per ml or 8 μg of sulbactam per ml and cefoxitin and cefotetan with and without 8 μg of sulbactam per ml. The results indicated that a minimum panel of five tests would provide maximum separation of extended-spectrum β-lactamase high AmpC, high K1, and other β-lactamase production in Enterobacteriaceae. These included cefpodoxime, cefpodoxime plus 4 μg of clavulanate per ml, ceftazidime, ceftriaxone, and ceftriaxone plus 8 μg of sulbactam per ml. Ceftriaxone plus 2 μg of clavulanate per ml could be substituted for cefpodoxime plus 4 μg of clavulanate per ml without altering the accuracy of the tests. This study indicated that tests with key β-lactam drugs, alone and in combination with β-lactamase inhibitors, could provide a convenient approach to the detection of a variety of β-lactamases in members of the family Enterobacteriaceae.
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Rudgers, Gary W., Wanzhi Huang, and Timothy Palzkill. "Binding Properties of a Peptide Derived from β-Lactamase Inhibitory Protein." Antimicrobial Agents and Chemotherapy 45, no. 12 (December 1, 2001): 3279–86. http://dx.doi.org/10.1128/aac.45.12.3279-3286.2001.
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ABSTRACT To overcome the antibiotic resistance mechanism mediated by β-lactamases, small-molecule β-lactamase inhibitors, such as clavulanic acid, have been used. This approach, however, has applied selective pressure for mutations that result in β-lactamases no longer sensitive to β-lactamase inhibitors. On the basis of the structure of β-lactamase inhibitor protein (BLIP), novel peptide inhibitors of β-lactamase have been constructed. BLIP is a 165-amino-acid protein that is a potent inhibitor of TEM-1 β-lactamase (K i = 0.3 nM). The cocrystal structure of TEM-1 β-lactamase and BLIP indicates that residues 46 to 51 of BLIP make critical interactions with the active site of TEM-1 β-lactamase. A peptide containing this six-residue region of BLIP was found to retain sufficient binding energy to interact with TEM-1 β-lactamase. Inhibition assays with the BLIP peptide reveal that, in addition to inhibiting TEM-1 β-lactamase, the peptide also inhibits a class A β-lactamase and a class C β-lactamase that are not inhibited by BLIP. The crystal structures of class A and C β-lactamases and two penicillin-binding proteins (PBPs) reveal that the enzymes have similar three-dimensional structures in the vicinity of the active site. This similarity suggests that the BLIP peptide inhibitor may have a broad range of activity that can be used to develop novel small-molecule inhibitors of various classes of β-lactamases and PBPs.
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Liang, Yu-He, Rong Gao, and Xiao-Dong Su. "Structural insights into the broadened substrate profile of the extended-spectrum β-lactamase OXY-1-1 fromKlebsiella oxytoca." Acta Crystallographica Section D Biological Crystallography 68, no. 11 (October 18, 2012): 1460–67. http://dx.doi.org/10.1107/s090744491203466x.
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Klebsiella oxytocais a pathogen that causes serious infections in hospital patients. It shows resistance to many clinically used β-lactam antibiotics by producing chromosomally encoded OXY-family β-lactamases. Here, the crystal structure of an OXY-family β-lactamase, OXY-1-1, determined at 1.93 Å resolution is reported. The structure shows that the OXY-1-1 β-lactamase has a typical class A β-lactamase fold and exhibits greater similarity to CTX-M-type β-lactamases than to TEM-family or SHV-family β-lactamases. It is also shown that the enzyme provides more space around the active cavity for theR1andR2substituents of β-lactam antibiotics. The half-positive/half-negative distribution of surface electrostatic potential in the substrate-binding pocket indicates the preferred properties of substrates or inhibitors of the enzyme. The results reported here provide a structural basis for the broadened substrate profile of the OXY-family β-lactamases.
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Gupta, Tanushree Barua, Malini Shariff, Thukral Ss, and S. s. Thukral. "IDENTIFICATION OF AMPC Β-LACTAMASE-PRODUCING CLINICAL ISOLATES OF ESCHERICHIA COLI." Asian Journal of Pharmaceutical and Clinical Research 10, no. 12 (December 1, 2017): 357. http://dx.doi.org/10.22159/ajpcr.2017.v10i12.21648.
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Objective: Indiscriminate use of β-lactam antibiotics has resulted in the emergence of β-lactamase enzymes. AmpC β-lactamases, in particular, confer resistance to penicillin, first-, second-, and third-generation cephalosporins as well as monobactams and are responsible for antibiotic resistance in nosocomial pathogens. Therefore, this study was undertaken to screen nosocomial Escherichia coli isolates for the presence and characterization of AmpC β-lactamases. The study also envisaged on the detection of inducible AmpC β-lactamases and extended-spectrum β-lactamases (ESBLs) in AmpC β-lactamase-producing E. coli.Methods: A total of 102 clinical isolates of E. coli, were subjected to cefoxitin screening, and screen-positive isolates were further subjected to inhibitor-based detection method, phenotypic confirmatory test, disc antagonism test, polymerase chain reaction (PCR), and isoelectric focusing (IEF).Results: In this study, 33% of E. coli were resistant to cefoxitin, of which 35% were found to be positive for AmpC β-lactamase by inhibitor-based phenotypic test. Of the AmpC-positive isolates, 83% were positive for ESBLs, whereas 25% were producing inducible AmpC β-lactamases. PCR and IEF showed CIT and EBC types of AmpC β-lactamases present in the tested isolates.Conclusion: Our study showed the presence of inducible AmpC enzymes and ESBLs in E. coli isolates and PCR identified more isolates to be AmpC producers.
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MATAGNE, André, Josette LAMOTTE-BRASSEUR, and Jean-Marie FRÈRE. "Catalytic properties of class A β-lactamases: efficiency and diversity." Biochemical Journal 330, no. 2 (March 1, 1998): 581–98. http://dx.doi.org/10.1042/bj3300581.
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β-Lactamases are the main cause of bacterial resistance to penicillins, cephalosporins and related β-lactam compounds. These enzymes inactivate the antibiotics by hydrolysing the amide bond of the β-lactam ring. Class A β-lactamases are the most widespread enzymes and are responsible for numerous failures in the treatment of infectious diseases. The introduction of new β-lactam compounds, which are meant to be ‘β-lactamase-stable’ or β-lactamase inhibitors, is thus continuously challenged either by point mutations in the ubiquitous TEM and SHV plasmid-borne β-lactamase genes or by the acquisition of new genes coding for β-lactamases with different catalytic properties. On the basis of the X-ray crystallography structures of several class A β-lactamases, including that of the clinically relevant TEM-1 enzyme, it has become possible to analyse how particular structural changes in the enzyme structures might modify their catalytic properties. However, despite the many available kinetic, structural and mutagenesis data, the factors explaining the diversity of the specificity profiles of class A β-lactamases and their amazing catalytic efficiency have not been thoroughly elucidated. The detailed understanding of these phenomena constitutes the cornerstone for the design of future generations of antibiotics.
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Drawz, Sarah M., and Robert A. Bonomo. "Three Decades of β-Lactamase Inhibitors." Clinical Microbiology Reviews 23, no. 1 (January 2010): 160–201. http://dx.doi.org/10.1128/cmr.00037-09.
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SUMMARYSince the introduction of penicillin, β-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial β-lactamases. β-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome β-lactamase-mediated resistance, β-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clinical practice. These inhibitors greatly enhance the efficacy of their partner β-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of seriousEnterobacteriaceaeand penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to β-lactam-β-lactamase inhibitor combinations. Furthermore, the prevalence of clinically relevant β-lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective inhibitors that can restore the activity of β-lactams. Here, we review the catalytic mechanisms of each β-lactamase class. We then discuss approaches for circumventing β-lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clinical and microbiological features of β-lactamase inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compounds and the chemical features of these agents that may contribute to a “second generation” of inhibitors. The goal for the next 3 decades will be to design inhibitors that will be effective for more than a single class of β-lactamases.
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Lahiri, Sushmita D., and Richard A. Alm. "Identification of Novel VEB β-Lactamase Enzymes and Their Impact on Avibactam Inhibition." Antimicrobial Agents and Chemotherapy 60, no. 5 (February 29, 2016): 3183–86. http://dx.doi.org/10.1128/aac.00047-16.
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ABSTRACTCeftazidime-avibactam has activity againstPseudomonas aeruginosaandEnterobacteriaceaeexpressing numerous class A and class C β-lactamases, although the ability to inhibit many minor enzyme variants has not been established. Novel VEB class A β-lactamases were identified during characterization of surveillance isolates. The cloned novel VEB β-lactamases possessed an extended-spectrum β-lactamase phenotype and were inhibited by avibactam in a concentration-dependent manner. The residues that comprised the avibactam binding pocket were either identical or functionally conserved. These data demonstrate that avibactam can inhibit VEB β-lactamases.
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de Jonge, Boudewijn L. M., James A. Karlowsky, Krystyna M. Kazmierczak, Douglas J. Biedenbach, Daniel F. Sahm, and Wright W. Nichols. "In VitroSusceptibility to Ceftazidime-Avibactam of Carbapenem-Nonsusceptible Enterobacteriaceae Isolates Collected during the INFORM Global Surveillance Study (2012 to 2014)." Antimicrobial Agents and Chemotherapy 60, no. 5 (February 29, 2016): 3163–69. http://dx.doi.org/10.1128/aac.03042-15.
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ABSTRACTThe activity of ceftazidime-avibactam was assessed against 961 isolates of meropenem-nonsusceptibleEnterobacteriaceae. Most meropenem-nonsusceptible metallo-β-lactamase (MBL)-negative isolates (97.7%) were susceptible to ceftazidime-avibactam. Isolates that carried KPC or OXA-48-like β-lactamases, both alone and in combination with extended-spectrum β-lactamases (ESBLs) and/or AmpC β-lactamases, were 98.7% and 98.5% susceptible to ceftazidime-avibactam, respectively. Meropenem-nonsusceptible, carbapenemase-negative isolates demonstrated 94.7% susceptibility to ceftazidime-avibactam. Ceftazidime-avibactam activity was compromised only in isolates for which carbapenem resistance was mediated through metallo-β-lactamases.
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Papp-Wallace, Krisztina M., Christopher R. Bethel, Melissa D. Barnes, Joseph D. Rutter, Magdalena A. Taracila, Saralee Bajaksouzian, Michael R. Jacobs, and Robert A. Bonomo. "AAI101, a Novel β-Lactamase Inhibitor: Microbiological and Enzymatic Profiling." Open Forum Infectious Diseases 4, suppl_1 (2017): S375. http://dx.doi.org/10.1093/ofid/ofx163.924.
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Abstract Background AAI101 is a novel β-lactamase inhibitor (BLI), active against ESBLs and other β-lactamases. AAI101 combined with cefepime (FEP) is in Phase 2 clinical trials. The objective of this study was to determine differences between AAI101 and tazobactam in their inhibition of selected β-lactamases of clinical relevance. Methods Isogenic E. coli strains expressing single clinically relevant β-lactamases were tested for susceptibility (broth microdilution MIC) to FEP, FEP/AAI101 and piperacillin-tazobactam (P/T). Periplasmic β-lactamase extracts from selected strains then were used to determine IC50s for AAI101 and for tazobactam. β-Lactamases with low IC50s for AAI101 were purified, and steady-state inactivation kinetics determined for AAI101 and for tazobactam. Results AAI101 restored activity of FEP against E. coli strains producing defined β-lactamases, and FEP/AAI101 was more potent than P/T (Table). Conclusion Addition of AAI101 enhances cefepime activity vs. a selected array of β-lactamases expressed in E. coli in an isogenic Background. The inhibitory kinetics of β-lactamases by AAI101 compared with those of tazobactam indicate different mechanisms of β-lactamase inhibition. Disclosures K. M. Papp-Wallace, Entasis: Grant Investigator, Research grant Allecra: Grant Investigator, Research grant Merck: Grant Investigator, Research grant; Roche: Grant Investigator, Research grant Allergan: Grant Investigator, Research grant M. R. Jacobs, Allecra: Grant Investigator, Research grant Roche: Grant Investigator, Research grant Shionogi: Grant Investigator, Research grant; R. A. Bonomo, Entasis: Grant Investigator, Research grant Allecra: Grant Investigator, Research grant Wockhardt: Grant Investigator, Research grant Merck: Grant Investigator, Research grant Roche: Grant Investigator, Research grant GSK: Grant Investigator, Research grant Allergan: Grant Investigator, Research grant Shionogi: Grant Investigator, Research grant
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Maiti, Samarendra N., Oludotun A. Phillips, Ronald G. Micetich, and David M. Livermore. "β-Lactamase Inhibitors: Agents to Overcome Bacterial Resistance." Current Medicinal Chemistry 5, no. 6 (December 1998): 441–56. http://dx.doi.org/10.2174/0929867305666220319110127.
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The extensive use of β-lactam antibiotics in hospitals and community has created major resistance problems leading to increased morbidity, mortality and health-care costs. Resistance is most often mediated by β-lactamases, which have emerged in both Gram-positive and Gram-negative bacteria. A novel approach to countering bacterial β-lactamases is the delivery of a β-lactam antibiotic in combination with a β-lactamase inhibitor. Several such combinations are currently available, containing inhibitors clavulanic acid, sulbactam and tazobactam. These inhibitors are not, however, active against all β-lactamases and the AmpC chromosomal enzymes that are hyperproduced by some enterobacteria and pseudomonas are a particular 'gap'. Moreover, genes for these AmpC enzymes have begun to escape to plasmids. Consequently, there is a growing need for new broad-spectrum β-lactamase inhibitors. This review offers an overview of synthetic β-lactamase inhibitors, emphasizing information on their structures, and highlighting their activity against various β-lactamases, particularly AmpC enzymes. Effective inhibition of AmpC enzymes are to be found among the penems and monobactams, but none of these has yet proved suitable for pharmaceutical development.
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Garau, Gianpiero, Anne Marie Di Guilmi, and Barry G. Hall. "Structure-Based Phylogeny of the Metallo-β-Lactamases." Antimicrobial Agents and Chemotherapy 49, no. 7 (July 2005): 2778–84. http://dx.doi.org/10.1128/aac.49.7.2778-2784.2005.
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ABSTRACTThe metallo-β-lactamases fall into two groups: Ambler class B subgroups B1 and B2 and Ambler class B subgroup B3. The two groups are so distantly related that there is no detectable sequence homology between members of the two different groups, but homology is clearly detectable at the protein structure level. The multiple structure alignment program MAPS has been used to align the structures of eight metallo-β-lactamases and five structurally homologous proteins from the metallo-β-lactamase superfamily, and that alignment has been used to construct a phylogenetic tree of the metallo-β-lactamases. The presence of genes fromEubacteria,Archaebacteria, andEukaryotaon that tree is consistent with a very ancient origin of the metallo-β-lactamase family.
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Lupiola-Gómez, P. A., Z. González-Lama, M. T. Tejedor-Junco, M. González-Martín, and J. L. Martín-Barrasa. "Group 1 β-lactamases ofAeromonas caviaeand their resistance to β-lactam antibiotics." Canadian Journal of Microbiology 49, no. 3 (March 1, 2003): 207–15. http://dx.doi.org/10.1139/w03-030.
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The contribution of β-lactamase production to β-lactam antibiotic resistance was examined in an Aeromonas caviae mutant strain, selected in vitro by cefotaxime and derived from a wild-type strain isolated in our laboratory from crude sewage. Both strains produced β-lactamase. The mutant strain (AC7m) produced β-lactamase constitutively, in contrast to the parental strain (AC7), which was inducible by cefoxitin. AC7m was regarded as a mutant from AC7, which over-expressed β-lactamase. The mutant strain showed a remarkable reduction in sensitivity to most of the β-lactam antibiotics tested, such as (i) aminopenicillins and their combinations with clavulanic acid and sulbactam, (ii) carboxypenicillins, (iii) ureidopenicillins, and (iv) cephalosporins. This strain remained susceptible to ceftazidime, imipenem, and aztreonam. Isoelectric focusing of sonic extracts revealed that both strains AC7 and AC7m shared a common major β-lactamase band at pI 6.5. The plasmid DNA assays showed that the β-lactamases expressed by each A. caviae strain were chromosomally encoded. Based on substrate and inhibitor profiles determined in sonic extracts for AC7 and AC7m, the enzymes displayed on isoelectric focusing at pI 6.5 were assigned to chromosomal Group 1 β-lactamases. Imipenem would therefore be the appropriate choice for therapy of infections caused by A. caviae β-lactamase over-expressing mutants.Key words: Aeromonas caviae, β-lactamases, antibiotic resistance.
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Moland, Ellen Smith, Jennifer A. Black, Jason Ourada, Mark D. Reisbig, Nancy D. Hanson, and Kenneth S. Thomson. "Occurrence of Newer β-Lactamases in Klebsiella pneumoniae Isolates from 24 U.S. Hospitals." Antimicrobial Agents and Chemotherapy 46, no. 12 (December 2002): 3837–42. http://dx.doi.org/10.1128/aac.46.12.3837-3842.2002.
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ABSTRACT Despite the discovery of novel β-lactamases such as extended-spectrum β-lactamases (ESBLs), imported AmpC, and carbapenem-hydrolyzing β-lactamases at least a decade ago, there remains a low level of awareness of their importance and how to detect them. There is a need to increase the levels of awareness of clinical laboratories about the detection of newer β-lactamases. Therefore, a study was conducted in 2000 to investigate the occurrence of these β-lactamases in Klebsiella pneumoniae isolates at 24 U.S. medical centers. To enhance the likelihood of detecting imported AmpC and carbapenem-hydrolyzing β-lactamases, participating laboratories were permitted to include archived strains (1996 to 2000) that were intermediate or resistant to either cefoxitin or imipenem. The β-lactamase production of 408 isolates positive by screening of 1,123 isolates was investigated by ESBL phenotypic confirmation tests; and for AmpC and carbapenem-hydrolyzing β-lactamases, three-dimensional tests, isoelectric focusing, β-lactamase inhibitor studies, spectrophotometric assays, induction assays, and molecular tests were used. ESBL-producing isolates were detected at 18 of the 24 sites (75%), imported AmpC-producing isolates were detected at 10 sites (42%), inducible imported AmpC-producing isolates were detected at 3 sites (12.5%), and a molecular class A carbapenem-hydrolyzing enzyme was detected at 1 site (4%). No class B or D carbapenem-hydrolyzing enzymes were detected. ESBLs and imported AmpC β-lactamases were detected at a significant number of sites, indicating widespread penetration of these enzymes into U.S. medical institutions. Because these enzymes may significantly affect therapeutic outcomes, it is vital that clinical laboratories be aware of them and be able to detect their occurrence.
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Nagano, Rie, Yuka Adachi, Hideaki Imamura, Koji Yamada, Terutaka Hashizume, and Hajime Morishima. "Carbapenem Derivatives as Potential Inhibitors of Various β-Lactamases, Including Class B Metallo-β-Lactamases." Antimicrobial Agents and Chemotherapy 43, no. 10 (October 1, 1999): 2497–503. http://dx.doi.org/10.1128/aac.43.10.2497.
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ABSTRACTA variety of 1β-methylcarbapenem derivatives were screened to identify inhibitors of IMP-1 metallo-β-lactamase, a class B β-lactamase, in an automated microassay system using nitrocefin as a substrate. The structure–inhibitory-activity relationship study revealed that three types of 1β-methylcarbapenems having benzothienylthio, dithiocarbamate, or pyrrolidinylthio moieties at the C-2 position showed good inhibitory activity. Among the compounds screened, J-110,441, having a benzothienylthio moiety at the C-2 position of 1β-methylcarbapenem, was the most potent inhibitor of class B metallo-β-lactamases withKivalues of 0.0037, 0.23, 1.00, and 0.83 μM for IMP-1 encoded by theblaIMPgene, CcrA fromBacteroides fragilis, L1 fromStenotrophomonas maltophilia, and type II fromBacillus cereus, respectively. In a further characterization study, J-110,441 also showed inhibitory activity against TEM-type class A serine β-lactamase and chromosomal class C serine β-lactamase fromEnterobacter cloacaewithKivalues of 2.54 and 0.037 μM, respectively. Combining imipenem or ceftazidime with J-110,441 had a synergistic effect on the antimicrobial activity against β-lactamase-producing bacteria. Against the isolates of IMP-1-producingSerratia marcescens, the MICs of imipenem decreased to levels ranging from 1/64 to 1/4 in the presence of one-fourth of the MIC of J-110,441. AgainstE. cloacaeproducing high levels of class C β-lactamase, the MIC of ceftazidime decreased from 64 to 4 μg/ml in the presence of 4 μg of J-110,441 per ml. This is the first report to describe a new class of inhibitor of class B and class C β-lactamases including transferable IMP-1 metallo-β-lactamases.
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Aneela, Syeda, Noor Ul-Ain, Samyyia Abrar, Muhammad Saeed, Shahida Hussain, Abdul Hannan, and Saba Riaz. "Distribution of Extended-spectrum β-lactamase and Metallo-β-lactamase-producing Pseudomonas aeruginosa in Tertiary Care Hospitals of Lahore, Pakistan." Journal of Islamabad Medical & Dental College 8, no. 1 (March 24, 2019): 23–28. http://dx.doi.org/10.35787/jimdc.v8i1.312.
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Background: Pseudomonas aeruginosa (P. aeruginosa) is an important bacterial pathogen most frequently associated with nosocomial infections, especially in immuno-compromised patients. Early detection of these life threatening, β-lactamase producing bacteria is essential for infection control and to prevent their dissemination. The aim of our study was to detect the presence of Extended-Spectrum β-Lactamase (ESBL) and Metallo-β-Lactamase (MBL) strains of Pseudomonas aeruginosa.Material and Methods: Eighty-eight identified strains of P. aeruginosa were collected from Chughtai Laboratories, Combined Military Hospital and Children Hospital, Lahore. These strains were sub-cultured and after confirming the cultural characteristics by Gram staining and colony morphology, manual biochemical identification was done. Susceptibility to various antibiotics and production of extended-spectrum β-lactamases (ESBLs) and metallo-β-lactamases (MBLs) were determined using modified Kirby Bauer disk diffusion method, double disk synergy test, combined disk synergy test (CDST) and inhibitor-potentiated disk diffusion test (IPD) respectively.Results: Out of eighty-eight strains tested, three were ESBL producers (3.4%) and eleven strains (12.5%) were found to be resistant to carbapenems. Of these, eight were MBL producers (72.7%). All these β-lactamase producing strains (14 strains) were multidrug-resistant (MDR). Piperacillin and piperacillin/tazobactam proved to be the most effective antibiotics in both types of β-lactamase producing strains.Conclusion: Our study shows noticeable emergence of β-lactamases (ESBLs & MBLs) in P. aeruginosa. All of these strains were MDR. It reveals a correlation of these β-lactamases with multidrug resistant genes.
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Wagner, R. Doug, Shemedia J. Johnson, Carl E. Cerniglia, and Bruce D. Erickson. "Bovine Intestinal Bacteria Inactivate and Degrade Ceftiofur and Ceftriaxone with Multiple β-Lactamases." Antimicrobial Agents and Chemotherapy 55, no. 11 (August 29, 2011): 4990–98. http://dx.doi.org/10.1128/aac.00008-11.
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ABSTRACTThe veterinary cephalosporin drug ceftiofur is rapidly degraded in the bovine intestinal tract. A cylinder-plate assay was used to detect microbiologically active ceftiofur, and high-performance liquid chromatography-mass spectrometry analysis was used to quantify the amount of ceftiofur remaining after incubation with bovine intestinal anaerobic bacteria, which were isolated from colon contents or feces from 8 cattle. Ninety-six percent of the isolates were able to inactivate ceftiofur to some degree, and 54% actually degraded the drug. None of 9 fungal isolates inactivated or degraded ceftiofur. Facultative and obligate anaerobic bacterial species that inactivated or degraded ceftiofur were identified with Vitek and Biolog systems, respectively. A subset of ceftiofur degraders also degraded the chemically similar drug ceftriaxone. Most of the species of bacteria that degraded ceftiofur belonged to the generaBacillusandBacteroides. PCR analysis of bacterial DNA detected specific β-lactamase genes.Bacillus cereusandB. mycoidesisolates produced extended-spectrum β-lactamases and metallo-β-lactamases. Seven isolates ofBacteroidesspp. produced multiple β-lactamases, including possibly CepA, and metallo-β-lactamases. Isolates ofEubacterium biforme,Bifidobacterium breve, and severalClostridiumspp. also produced ceftiofur-degrading β-lactamases. An agar gel overlay technique on isoelectric focusing separations of bacterial lysates showed that β-lactamase enzymes were sufficient to degrade ceftiofur. These results suggest that ceftiofur is inactivated nonenzymatically and degraded enzymatically by multiple β-lactamases from bacteria in the large intestines of cattle.
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Thakur, Rameshwari, Kumar Atul, Chaudhary Varsha, Singh Paramjit, Sharma Vk, and Nidhi Agarwal. "PREVALENCE OF VARIOUS BETA LACTAMASES AMONG GRAM NEGATIVE BACILLI IN URINARY ISOLATES FROM PATIENTS IN A TERTIARY CARE HOSPITAL OF NORTHERN INDIA." Asian Journal of Pharmaceutical and Clinical Research 10, no. 4 (April 1, 2017): 129. http://dx.doi.org/10.22159/ajpcr.2017.v10i4.16291.
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Objective: Urinary tract infections are considered among the most common infections, occurring either in the community or health-care setting. We are left with very few options for the treatment due to rapid development of antibiotic resistance among the organisms. To find out the prevalence of various types of β-lactamases among urinary isolates.Methods: Seven antibiotic discs (HiMedia) were placed in combinations and approximation in a particular sequence on a 90 mm diameter MuellerHintonagar plate.Results: Out of a total 165 urinary isolates, 66 (40%) isolates were positive for extended spectrum β-lactamase (ESBL) production, AmpC β-lactamases(AmpC) activity was present in 31 (18.78%) isolates, co-production of both ESBL and AmpC was seen in 16 (9.69%) isolates, 3 (1.81%) isolatesproduced metallo β-lactamase (MBL), 2 (1.21%) isolates produced both MBL, and ESBL and 1 (0.60%) isolates were positive for inducible third generation cephalosporin resistance.Conclusion: With the presence of such high prevalence of various β-lactamases in clinical isolates of gram-negative bacilli and also other types ofantibiotic resistance, antibiotic policy should be made, and strict adherence should be followed.Keywords: Extended spectrum β-lactamase, AmpC β-lactamase, Metallo β-lactamase.
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Queenan, Anne Marie, Wenchi Shang, Malgosia Kania, Malcolm G. P. Page, and Karen Bush. "Interactions of Ceftobiprole with β-Lactamases from Molecular Classes A to D." Antimicrobial Agents and Chemotherapy 51, no. 9 (June 25, 2007): 3089–95. http://dx.doi.org/10.1128/aac.00218-07.
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ABSTRACT The interactions of ceftobiprole with purified β-lactamases from molecular classes A, B, C, and D were determined and compared with those of benzylpenicillin, cephaloridine, cefepime, and ceftazidime. Enzymes were selected from functional groups 1, 2a, 2b, 2be, 2d, 2e, and 3 to represent β-lactamases from organisms within the antibacterial spectrum of ceftobiprole. Ceftobiprole was refractory to hydrolysis by the common staphylococcal PC1 β-lactamase, the class A TEM-1 β-lactamase, and the class C AmpC β-lactamase but was labile to hydrolysis by class B, class D, and class A extended-spectrum β-lactamases. Cefepime and ceftazidime followed similar patterns. In most cases, the hydrolytic stability of a substrate correlated with the MIC for the producing organism. Ceftobiprole and cefepime generally had lower MICs than ceftazidime for AmpC-producing organisms, particularly AmpC-overexpressing Enterobacter cloacae organisms. However, all three cephalosporins were hydrolyzed very slowly by AmpC cephalosporinases, suggesting that factors other than β-lactamase stability contribute to lower ceftobiprole and cefepime MICs against many members of the family Enterobacteriaceae.
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Nerway, Sozan M., and Muna S. Al-Delaimi. "Phenotypic and Molecular Detection of Extended Spectrum Beta-Lactamases Producing-Bacteria Isolated From Pregnant Women With Genital Tract Infection in Duhok Governorate." Science Journal of University of Zakho 9, no. 2 (June 30, 2021): 80–88. http://dx.doi.org/10.25271/sjuoz.2021.9.2.784.
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Beta-lactamase producing bacteria have a worldwide distribution with a high degree of prevalence in both community and hospital. Furthermore, multidrug resistant (MDR) and extended spectrum β-lactamases (ESBL) producing bacterial isolates from women patients may limit treatment options available. This study was designed to determine the frequency of bacterial isolates associated with genital tract infection in pregnant women and their antimicrobial resistance profile and to assess the prevalence of extended spectrum β-lactamases producing bacteria. Demonstrating the β-lactamase genes (blaTEM, blaSHV and blaCTX-M) by using polymerase chain reaction (PCR) assay with specific primers, was carried out on patients who were admitted to Maternity and Obstetric Hospital in Duhok city from November 2018 to October 2019. A total of 100 high vaginal swabs were collected from pregnant women patients between the ages 18-45 years. All clinical samples were cultured and standard microbiological methods were used to identify bacterial isolates, then confirmed by Vitek®2 compact automated system. All gram negative bacterial isolates were studied phenotypically and genotypically for extended spectrum β-lactamases-production. Out of 100 vaginal swabs, 88% confirmed positive culture; 90.9% of which were bacterial isolates. From the total bacterial isolates, 38.8% were gram negative bacteria, with a predominant 54.8% Klebsiella pneumoniae followed by Escherichia coli 35.5%. 54.8% of the isolates were characterized as multidrug resistance isolates, 29% isolates were extensive drug resistance, and no pan drug resistance were detected. Among these, the commonest extended spectrum β-lactamases producing isolates were Escherichia coli 81.8% followed by, Klebsiella pneumoniae 58.8%. Extended spectrum β-lactamases-producing isolates have showed significantly higher resistance than non- extended spectrum β-lactamases producing isolates to third and fourth generation cephalosporins. CTX-M was the most common β-lactamase gene 73.7% among extended spectrum β-lactamase producing strains, followed by blaSHV, 57.9% and blaTEM 52.6%, 21.1% had combination of all bla genes, 15.8% had CTX-M only and combination of blaCTX-M with blaSHV and blaTEM. 10.5% among extended spectrum β-lactamases producing isolates carried SHV type only and in combination with TEM type while TEM gene were observed in 5.3%. We concluded that the drug resistant isolates were common, worryingly high and it may limit treatment options available. In this study a high level of the blaCTX-M gene was demonstrated among extended spectrum β-lactamases producing isolates.
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Suvorov, Maxim, Sergei B. Vakulenko, and Shahriar Mobashery. "Cytoplasmic-Membrane Anchoring of a Class A β-Lactamase and Its Capacity in Manifesting Antibiotic Resistance." Antimicrobial Agents and Chemotherapy 51, no. 8 (May 14, 2007): 2937–42. http://dx.doi.org/10.1128/aac.00011-07.
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ABSTRACT Bacterial β-lactamases are the major causes of resistance to β-lactam antibiotics. Three classes of these enzymes are believed to have evolved from ancestral penicillin-binding proteins (PBPs), enzymes responsible for bacterial cell wall biosynthesis. Both β-lactamases and PBPs are able to efficiently form acyl-enzyme species with β-lactam antibiotics. In contrast to β-lactamases, PBPs are unable to efficiently turn over antibiotics and therefore are susceptible to inhibition by β-lactam compounds. Although both PBPs and gram-negative β-lactamases operate in the periplasm, PBPs are anchored to the cytoplasmic membrane, but β-lactamases are not. It is believed that β-lactamases shed the membrane anchor in the course of evolution. The significance of this event remains unclear. In an attempt to demonstrate any potential influence of the membrane anchor on the overall biological consequences of β-lactamases, we fused the TEM-1 β-lactamase to the C-terminal membrane-anchor of penicillin-binding protein 5 (PBP5) of Escherichia coli. The enzyme was shown to express well in E. coli and was anchored to the cytoplasmic membrane. Expression of the anchored enzyme did not result in any changes in antibiotic resistance pattern of bacteria or growth rates. However, in the process of longer coincubation, the organism that harbored the plasmid for the anchored TEM-1 β-lactamase lost out to the organism transformed by the plasmid for the nonanchored enzyme over a period of 8 days of continuous growth. The effect would appear to be selection of a variant that eliminates the problematic protein through elimination of the plasmid that encodes it and not structural or catalytic effects at the protein level. It is conceivable that an evolutionary outcome could be the shedding of the sequence for the membrane anchor or alternatively evolution of these enzymes from nonanchored progenitors.
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Yang, Katherine, and B. Joseph Guglielmo. "Diagnosis and Treatment of Extended-Spectrum and AmpC β-Lactamase–Producing Organisms." Annals of Pharmacotherapy 41, no. 9 (September 2007): 1427–35. http://dx.doi.org/10.1345/aph.1k213.
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Objective: To review the laboratory diagnosis of extended-spectrum β-lactamase (ESBL) and AmpC β-lactamase–producing bacteria and evaluate potential treatment options. Data Sources: A PubMed search, restricted to English-language articles, was conducted (1966–May 2007) using the search terms ESBL, AmpC, diagnosis, detection, carbapenem, ertapenem, fluoroquinolone, cephalosporin, cefepime, tigecycline, and colistin. Additional references were identified through review of bibliographies of identified articles. Study Selection and Data Extraction: All studies that evaluated laboratory methods for the detection of ESBLs and AmpC β-lactamases and/or the treatment of these organisms were reviewed. All articles that were deemed to be clinically pertinent were included and critically evaluated. Data Synthesis: Numerous laboratory techniques are available for the detection of ESBLs. In contrast, laboratory techniques for detection of AmpC β-lactamases are limited, particularly for plasmid-mediated AmpC β-lactamases. Routine microbiologic testing may not detect ESBLs or AmpC β-lactamases. Optimal antibiotic treatment options are derived from limited observational studies and case reports. Randomized clinical trials evaluating appropriate antibiotic treatment options are lacking. In vitro susceptibility does not always correlate with clinical outcomes. The use of imipenem was associated with the lowest incidence of mortality in patients with bacteremia due to ESBL-producing organisms. Conclusions: Laboratory detection of ESBLs for most organisms is possible with Clinical and Laboratory Standards Institute–recommended testing. However, these tests can be associated with both false negative and false positive results, particularly with organisms that harbor both ESBL- and plasmid-mediated AmpC β-lactamases. No established guidelines exist for the detection of AmpC β-lactamases. Imipenem and meropenem are superior to other antibiotics for the treatment of serious infections due to ESBL and AmpC β-lactamase–producing gram-negative bacteria. While in vitro data demonstrate that tigecycline, ertapenem, and colistin might be potential choices, clinical experience is lacking.
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Gangadharappa, Bhavya, Manjunath Dammalli, and Sharath Rajashekarappa. "β-Lactams and β-Lactamase Inhibitors: Unlocking their potential to address drug resistance." Research Journal of Biotechnology 16, no. 8 (July 25, 2021): 151–58. http://dx.doi.org/10.25303/168rjbt15121.
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Antibiotics such as β-lactams are one of the most widely used antibacterial drug classes in the world. The invention of the first β-lactam antibiotic (Penicillin) is regarded as a symbolic landmark in the history of modern chemotherapy. Since that time, several other β-lactam antibiotics have been added to the treatment, revolutionising the treatment of bacterial infections. Antibacterial efficacy of the β-lactams has been kept in check by the emergence of bacterial resistance. One of the most studied and common resistance mechanisms is the expression of β-lactamase enzymes. The invention of β-lactamase inhibitors which restore the efficacy of β-lactam antibiotics, has been a significant advance in the fight against microbial drug resistance. However, many recently identified β-lactamases are not inactivated by the presently available inhibitors. Despite the fact that these inhibitors may not be effective against all β-lactamases, their implementation is still welcome. This review focuses on the development of β-lactam antibiotics and the mechanism of action. It also covers the diversity of β-lactamases with an emphasis on rising bacterial resistance. It provides a summary on β-lactamase inhibitors with a focus on restoring antibiotic efficacy and the various computational approaches used in inhibitor discovery. Finally, we outlined an update on research activities aimed at discovering and developing novel β-lactamase inhibitors.
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Koh, Tse Hsien. "Gram-negative Resistance in Singapore: A Historical Perspective." Annals of the Academy of Medicine, Singapore 37, no. 10 (October 15, 2008): 847–54. http://dx.doi.org/10.47102/annals-acadmedsg.v37n10p847.
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In the past 3 decades, classical extended-spectrum β-lactamases (ESBLs) have probably been the main contributors to gram-negative antimicrobial resistance in Singapore. These appear to be being replaced by the newer CTX-M ESBLs. Metallo-β-lactamases are found in Pseudomonas aeruginosa but do not seem to have spread widely in Acinetobacter spp. and Enterobacteriaceae. Carbapenem-hydrolysing oxacillinases are prevalent in multidrug-resistant Acinetobacter spp. More insidious developments include the emergence of plasmid AmpC β-lactamases and multifactorial quinolone resistance in Enterobacteriaceae. Key words: AmpC, Carbapenemase, Extended-spectrum β-lactamase, Oxacillinase, Quinolone
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Ehrhardt, Anton F., Christine C. Sanders, and Ellen S. Moland. "Use of an Isogenic Escherichia coliPanel To Design Tests for Discrimination of β-Lactamase Functional Groups of Enterobacteriaceae." Antimicrobial Agents and Chemotherapy 43, no. 3 (March 1, 1999): 630–33. http://dx.doi.org/10.1128/aac.43.3.630.
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ABSTRACT A study was designed to determine if an isogenic panel ofEscherichia coli strains containing many different β-lactamases could be used for the preliminary screening of a large number of β-lactam agents to identify which might be most useful in the development of a definitive test for specific β-lactamases found among the members of family Enterobacteriaceae. The susceptibilities of 46 strains, comprising the isogenic panel, to expanded-spectrum cephalosporins, cephamycins, and aztreonam were determined in the presence and absence of β-lactamase inhibitors in broth microdilution tests. The results indicated that strains producing extended-spectrum β-lactamases (ESBLs) could be distinguished from strains producing other Bush-Jacoby-Medeiros functional group 2 or group 1 β-lactamases. For strains producing group 1 β-lactamases, cefpodoxime and ceftazidime MICs were ≥4 μg/ml and addition of clavulanate did not reduce the MICs more than fourfold. For strains producing group 2 enzymes other than ESBLs, cefpodoxime and ceftazidime MICs were ≤2 μg/ml. With a single exception (ceftazidime for the strain producing SHV-3), among strains producing ESBLs, cefpodoxime and ceftazidime MICs were ≥4 μg/ml and addition of clavulanate reduced the MICs by more than eightfold. Cephamycins could also be used to discriminate between strains producing group 1 β-lactamases and ESBLs, since only the former required cefotetan concentrations as high as 8 μg/ml or cefoxitin concentrations of >16 μg/ml for inhibition. Other cephalosporins provided some discrimination between the various β-lactamase producers, although they were not as reliable as either cefpodoxime or ceftazidime. These results indicate the utility of an isogenic panel for identification of candidate drugs among many for further testing with clinical isolates of the familyEnterobacteriaceae to determine the best agents for detection of specific β-lactamases in this family.
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Lang, Pauline A., Anete Parkova, Thomas M. Leissing, Karina Calvopiña, Ricky Cain, Alen Krajnc, Tharindi D. Panduwawala, et al. "Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli." Biomolecules 10, no. 6 (June 12, 2020): 899. http://dx.doi.org/10.3390/biom10060899.
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Resistance to β-lactam antibacterials, importantly via production of β-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) β-lactamases. In combination with cefepime, the bicyclic boronate taniborbactam is in phase 3 clinical trials for treatment of complicated urinary tract infections. We report kinetic and crystallographic studies on the inhibition of AmpC, the class C β-lactamase from Escherichia coli, by bicyclic boronates, including taniborbactam, with different C-3 side chains. The combined studies reveal that an acylamino side chain is not essential for potent AmpC inhibition by active site binding bicyclic boronates. The tricyclic form of taniborbactam was observed bound to the surface of crystalline AmpC, but not at the active site, where the bicyclic form was observed. Structural comparisons reveal insights into why active site binding of a tricyclic form has been observed with the NDM-1 MBL, but not with other studied β-lactamases. Together with reported studies on the structural basis of inhibition of class A, B and D β-lactamases, our data support the proposal that bicyclic boronates are broad-spectrum β-lactamase inhibitors that work by mimicking a high energy ‘tetrahedral’ intermediate. These results suggest further SAR guided development could improve the breadth of clinically useful β-lactamase inhibition.
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Carcione, Davide, Claudia Siracusa, Adela Sulejmani, Valerio Leoni, and Jari Intra. "Old and New Beta-Lactamase Inhibitors: Molecular Structure, Mechanism of Action, and Clinical Use." Antibiotics 10, no. 8 (August 17, 2021): 995. http://dx.doi.org/10.3390/antibiotics10080995.
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The β-lactams have a central place in the antibacterial armamentarium, but the increasing resistance to these drugs, especially among Gram-negative bacteria, is becoming one of the major threats to public health worldwide. Treatment options are limited, and only a small number of novel antibiotics are in development. However, one of the responses to this threat is the combination of β-lactam antibiotics with β-lactamase inhibitors, which are successfully used in the clinic for overcoming resistance by inhibiting β-lactamases. The existing inhibitors inactivate most of class A and C serine β-lactamases, but several of class D and B (metallo-β-lactamase) are resistant. The present review provides the status and knowledge concerning current β-lactamase inhibitors and an update on research efforts to identify and develop new and more efficient β-lactamase inhibitors.
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Hu, Rouh-Mei, Kai-Hung Chiang, Yi-Chih Chang, and Tsuey-Ching Yang. "Characterization of the charge variants of L2 β-lactamase in Stenotrophomonas maltophilia." Journal of Medical Microbiology 58, no. 3 (March 1, 2009): 318–21. http://dx.doi.org/10.1099/jmm.0.000380-0.
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Stenotrophomonas maltophilia KH has two acid β-lactamases with isoelectric points (pIs) of 4.6 and 5.4, and several basic β-lactamases (pIs >7.0) that produce a ladder-shaped pattern by IEF. An isogenic L2 mutant, KHL2xylE, was constructed by gene replacement. From IEF and native PAGE zymograms of strains KH and KHL2xylE, it was demonstrated that the basic β-lactamases and the acid β-lactamase with pI 5.4 are encoded by the same L2 gene and that the active types of these L2 charge variants were dependent on the buffer pH. The β-lactamase activities of these L2 charge variants in phosphate buffer at pH 7.0 and 8.0 were 1075±29 and 1114±81 U mg−1, respectively. These results indicate that L2 charge variants give S. maltophilia a better chance of adapting and surviving in response to changes in the environment.
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Livermore, David M., Marina Warner, Shazad Mushtaq, and Neil Woodford. "Interactions of OP0595, a Novel Triple-Action Diazabicyclooctane, with β-Lactams against OP0595-Resistant Enterobacteriaceae Mutants." Antimicrobial Agents and Chemotherapy 60, no. 1 (November 9, 2015): 554–60. http://dx.doi.org/10.1128/aac.02184-15.
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ABSTRACTOP0595 is a novel diazabicyclooctane which, like avibactam, inhibits class A and C β-lactamases. In addition, unlike avibactam, it has antibacterial activity, with MICs of 0.5 to 4 μg/ml for most members of the familyEnterobacteriaceae, owing to inhibition of PBP2; moreover, it acts synergistically with PBP3-active β-lactams independently of β-lactamase inhibition, via an “enhancer effect.”Enterobacteriaceaemutants stably resistant to 16 μg/ml OP0595 were selected on agar at frequencies of approximately 10−7. Unsurprisingly, OP0595 continued to potentiate substrate β-lactams against mutants derived fromEnterobacteriaceaewith OP0595-inhibited class A and C β-lactamases. Weaker potentiation of partners, especially aztreonam, cefepime, and piperacillin—less so meropenem—remained frequent for OP0595-resistantEnterobacteriaceaemutants lacking β-lactamases or with OP0595-resistant metallo-β-lactamases (MBLs), indicating that the enhancer effect is substantially retained even when antibiotic activity is lost.
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Jacobs, Lian M. C., Patrick Consol, and Yu Chen. "Drug Discovery in the Field of β-Lactams: An Academic Perspective." Antibiotics 13, no. 1 (January 8, 2024): 59. http://dx.doi.org/10.3390/antibiotics13010059.
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β-Lactams are the most widely prescribed class of antibiotics that inhibit penicillin-binding proteins (PBPs), particularly transpeptidases that function in peptidoglycan synthesis. A major mechanism of antibiotic resistance is the production of β-lactamase enzymes, which are capable of hydrolyzing β-lactam antibiotics. There have been many efforts to counter increasing bacterial resistance against β-lactams. These studies have mainly focused on three areas: discovering novel inhibitors against β-lactamases, developing new β-lactams less susceptible to existing resistance mechanisms, and identifying non-β-lactam inhibitors against cell wall transpeptidases. Drug discovery in the β-lactam field has afforded a range of research opportunities for academia. In this review, we summarize the recent new findings on both β-lactamases and cell wall transpeptidases because these two groups of enzymes are evolutionarily and functionally connected. Many efforts to develop new β-lactams have aimed to inhibit both transpeptidases and β-lactamases, while several promising novel β-lactamase inhibitors have shown the potential to be further developed into transpeptidase inhibitors. In addition, the drug discovery progress against each group of enzymes is presented in three aspects: understanding the targets, screening methodology, and new inhibitor chemotypes. This is to offer insights into not only the advancement in this field but also the challenges, opportunities, and resources for future research. In particular, cyclic boronate compounds are now capable of inhibiting all classes of β-lactamases, while the diazabicyclooctane (DBO) series of small molecules has led to not only new β-lactamase inhibitors but potentially a new class of antibiotics by directly targeting PBPs. With the cautiously optimistic successes of a number of new β-lactamase inhibitor chemotypes and many questions remaining to be answered about the structure and function of cell wall transpeptidases, non-β-lactam transpeptidase inhibitors may usher in the next exciting phase of drug discovery in this field.
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Page, Malcolm G. P., Clothilde Dantier, Eric Desarbre, Bérangère Gaucher, Klaus Gebhardt, and Anne Schmitt-Hoffmann. "In VitroandIn VivoProperties of BAL30376, a β-Lactam and Dual β-Lactamase Inhibitor Combination with Enhanced Activity against Gram-Negative Bacilli That Express Multiple β-Lactamases." Antimicrobial Agents and Chemotherapy 55, no. 4 (January 18, 2011): 1510–19. http://dx.doi.org/10.1128/aac.01370-10.
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ABSTRACTBAL30376 is a triple combination comprising a siderophore monobactam,BAL19764; a novel bridged monobactam,BAL29880, which specifically inhibits class C β-lactamases; and clavulanic acid, which inhibits many class A and some class D β-lactamases. The MIC90was ≤4 μg/ml (expressed as the concentration ofBAL19764) for most species of theEnterobacteriaceaefamily, including strains that produced metallo-β-lactamases and were resistant to all of the other β-lactams tested. The MIC90forStenotrophomonas maltophiliawas 2 μg/ml, for multidrug-resistant (MDR)Pseudomonas aeruginosait was 8 μg/ml, and for MDRAcinetobacterandBurkholderiaspp. it was 16 μg/ml. The presence of the class C β-lactamase inhibitorBAL29880contributed significantly to the activity ofBAL30376against strains ofCitrobacter freundii,Enterobacterspecies,Serratia marcescens, andP. aeruginosa. The presence of clavulanic acid contributed significantly to the activity against many strains ofEscherichia coliandKlebsiella pneumoniaethat produced class A extended-spectrum β-lactamases. The activity ofBAL30376against strains with metallo-β-lactamases was largely attributable to the intrinsic stability of the monobactamBAL19764toward these enzymes. Considering its three components,BAL30376was unexpectedly refractory toward the development of stable resistance.
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CHIRICA, LAURA-CHRISTINA, TÜLİN GÜRAY, G. CANDAN GÜRAKAN, and T. FARUK BOZOĞLU. "Characterization of Extracellular β-Lactamases from Penicillin G-Resistant Cells of Streptococcus thermophilus." Journal of Food Protection 61, no. 7 (July 1, 1998): 896–98. http://dx.doi.org/10.4315/0362-028x-61.7.896.
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In this study, biochemical properties of two extracellular β-lactamases produced by penicillin-resistant Streptococcus thermophilus cells were investigated. Both β-lactamases showed specificity for penicillins but not for cephaloridins. The β-lactamases exhibited different affinities for penicillin G. The one with the higher molecular weight (FI) had a Km value of 3.44 μM and a Vmax value of 8.33 μmol/min/mg of protein, whereas the β-lactamase with the lower molecular weight (FII) had a Km value of 4.76 μM and a Vmax value of 3.13 μmol/min/mg of protein. Both β-lactamases were inhibited by iodine, copper sulfate, and iron sulfate but not by EDTA. The optimal pH ranged between 6 and 7, and the optimal temperatures were between 40 and 45°C for both enzymes.
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Singh, Priyanka. "The incidence of AmpC β-lactamases producing Klebsiella pneumoniae subspecies pneumoniae." International Journal of Research in Medical Sciences 6, no. 4 (March 28, 2018): 1169. http://dx.doi.org/10.18203/2320-6012.ijrms20181043.
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Background: AmpC β- lactamases in the clinical isolates reduces the therapeutic value of β- lactam- β-lactam inhibitor combinations. if not detected can be disseminated in the hospital environment and pose a serious therapeutic challenge. Hence present study is undertaken to detect the incidence of AmpC β -lactamases producing Klebsiella pneumoniae subspecies pneumoniae out of total 300 Klebsiella pneumoniae subspecies pneumoniae isolated from different clinical samples of the patient attending Jawaharlal Nehru Medical College and its hospital in Dept of Microbiology.Methods: Isolates are screened for presumptive AmpC production by testing their susceptibility to Cefoxitin using Kirby-Bauer disk diffusion method. Phenotypic confirmatory tests for detection of AmpC β- lactamases by Modified three dimentional test, Amp C disc test, Amp C disc test with Inhibitor (Boronic Acid) based disc potentiation test.Results: In our present study 75 (25%) Klebsiella pneumoniae strains were positive for AmpC β lactamases production either alone or in combinations with other β- lactamases. 75 strains were positive for AmpC β-lactamase (25%). These 75 strains were further confirmed by E Test.Conclusions: Overproduction of AmpC β- lactamases by mutation is responsible for resistance. if not detected can be pose a serious therapeutic challenge. So, its detection improves the therapeutic outcome in patient care.
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Bethel, Christopher R., Magdalena Taracila, Teresa Shyr, Jodi M. Thomson, Anne M. Distler, Kristine M. Hujer, Andrea M. Hujer, et al. "Exploring the Inhibition of CTX-M-9 by β-Lactamase Inhibitors and Carbapenems." Antimicrobial Agents and Chemotherapy 55, no. 7 (May 9, 2011): 3465–75. http://dx.doi.org/10.1128/aac.00089-11.
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ABSTRACTCurrently, CTX-M β-lactamases are among the most prevalent and most heterogeneous extended-spectrum β-lactamases (ESBLs). In general, CTX-M enzymes are susceptible to inhibition by β-lactamase inhibitors. However, it is unknown if the pathway to inhibition by β-lactamase inhibitors for CTX-M ESBLs is similar to TEM and SHV β-lactamases and why bacteria possessing only CTX-M ESBLs are so susceptible to carbapenems. Here, we have performed a kinetic analysis and timed electrospray ionization mass spectrometry (ESI-MS) studies to reveal the intermediates of inhibition of CTX-M-9, an ESBL representative of this family of enzymes. CTX-M-9 β-lactamase was inactivated by sulbactam, tazobactam, clavulanate, meropenem, doripenem, ertapenem, and a 6-methylidene penem, penem 1.Kivalues ranged from 1.6 ± 0.3 μM (mean ± standard error) for tazobactam to 0.02 ± 0.01 μM for penem 1. Before and after tryptic digestion of the CTX-M-9 β-lactamase apo-enzyme and CTX-M-9 inactivation by inhibitors (meropenem, clavulanate, sulbactam, tazobactam, and penem 1), ESI-MS and matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) identified different adducts attached to the peptide containing the active site Ser70 (+52, 70, 88, and 156 ± 3 atomic mass units). This study shows that a multistep inhibition pathway results from modification or fragmentation with clavulanate, sulbactam, and tazobactam, while a single acyl enzyme intermediate is detected when meropenem and penem 1 inactivate CTX-M-9 β-lactamase. More generally, we propose that Arg276 in CTX-M-9 plays an essential role in the recognition of the C3carboxylate of inhibitors and that the localization of this positive charge to a “region of the active site” rather than a specific residue represents an important evolutionary strategy used by β-lactamases.
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Mammeri, Hedi, Samuel Bellais, and Patrice Nordmann. "Chromosome-Encoded β-Lactamases TUS-1 and MUS-1 from Myroides odoratus and Myroides odoratimimus (Formerly Flavobacterium odoratum), New Members of the Lineage of Molecular Subclass B1 Metalloenzymes." Antimicrobial Agents and Chemotherapy 46, no. 11 (November 2002): 3561–67. http://dx.doi.org/10.1128/aac.46.11.3561-3567.2002.
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ABSTRACT Myroides odoratus and Myroides odoratimimus (formerly designated in a single species as Flavobacterium odoratum) are gram-negative aerobes and sources of nosocomial infections in humans. They have variable susceptibility to β-lactams and a decreased susceptibility to carbapenems. Using genomic DNAs of M. odoratus CIP 103105 and M. odoratimimus CIP 103073 reference strains, shotgun cloning of β-lactamase genes was performed, followed by protein expression in Escherichia coli. The deduced amino acid sequences of these β-lactamase genes revealed that TUS-1 and MUS-1 from M. odoratus CIP 103105 and M. odoratimimus CIP 103073, respectively, shared 73% amino acid identity. Mature proteins TUS-1 and MUS-1, with pI values of 7.8 and 5.2, respectively, had relative molecular masses of ca. 26 kDa. These β-lactamases are members of the subclass B1 of metallo-β-lactamases and are distantly related to other metalloenzymes, being most closely related to IND-1 from Chryseobacterium indologenes (42% amino acid identity). However, phylogenic analysis showed that TUS-1 and MUS-1 belong to the same phylogenic lineage of subclass B1 enzymes that groups the subclass B1 β-lactamases of Flavobacterium species. Kinetic parameters of purified β-lactamases TUS-1 and MUS-1 detailed their hydrolysis spectra, which encompass most β-lactams except aztreonam. β-Lactamases TUS-1 and MUS-1 were classified in functional subgroup 3a of metalloenzymes. This work further characterizes chromosome-encoded metalloenzymes from Flavobacteriaceae species that explain at least part of their intrinsic resistance to β-lactams.
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Flores, Anthony R., Linda M. Parsons, and Martin S. Pavelka,. "Genetic analysis of the β-lactamases of Mycobacterium tuberculosis and Mycobacterium smegmatis and susceptibility to β-lactam antibiotics." Microbiology 151, no. 2 (February 1, 2005): 521–32. http://dx.doi.org/10.1099/mic.0.27629-0.
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Mycobacteria produce β-lactamases and are intrinsically resistant to β-lactam antibiotics. In addition to the β-lactamases, cell envelope permeability and variations in certain peptidoglycan biosynthetic enzymes are believed to contribute to β-lactam resistance in these organisms. To allow the study of these additional mechanisms, mutants of the major β-lactamases, BlaC and BlaS, were generated in the pathogenic Mycobacterium tuberculosis strain H37Rv and the model organism Mycobacterium smegmatis strain PM274. The mutants M. tuberculosis PM638 (ΔblaC1) and M. smegmatis PM759 (ΔblaS1) showed an increase in susceptibility to β-lactam antibiotics, as determined by disc diffusion and minimal inhibitory concentration (MIC) assays. The susceptibility of the mutants, as assayed by disc diffusion tests, to penicillin-type β-lactam antibiotics was affected most, compared to the cephalosporin-type β-lactam antibiotics. The M. tuberculosis mutant had no detectable β-lactamase activity, while the M. smegmatis mutant had a residual type 1 β-lactamase activity. We identified a gene, blaE, encoding a putative cephalosporinase in M. smegmatis. A double β-lactamase mutant of M. smegmatis, PM976 (ΔblaS1ΔblaE : : res), had no detectable β-lactamase activity, but its susceptibility to β-lactam antibiotics was not significantly different from that of the ΔblaS1 parental strain, PM759. The mutants generated in this study will help determine the contribution of other β-lactam resistance mechanisms in addition to serving as tools to study the biology of peptidoglycan biosynthesis in these organisms.
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Cullmann, Wolfgang. "Interaction of β-Lactamase Inhibitors with Various β-Lactamases." Chemotherapy 36, no. 3 (1990): 200–208. http://dx.doi.org/10.1159/000238767.
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Bush, Karen, and Patricia A. Bradford. "Interplay between β-lactamases and new β-lactamase inhibitors." Nature Reviews Microbiology 17, no. 5 (March 5, 2019): 295–306. http://dx.doi.org/10.1038/s41579-019-0159-8.
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Voladri, Rama Kishan R., David L. Lakey, Steven H. Hennigan, Barbara E. Menzies, Kathryn M. Edwards, and Douglas S. Kernodle. "Recombinant Expression and Characterization of the Major β-Lactamase of Mycobacterium tuberculosis." Antimicrobial Agents and Chemotherapy 42, no. 6 (June 1, 1998): 1375–81. http://dx.doi.org/10.1128/aac.42.6.1375.
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ABSTRACT New antibiotic regimens are needed for the treatment of multidrug-resistant tuberculosis. Mycobacterium tuberculosis has a thick peptidoglycan layer, and the penicillin-binding proteins involved in its biosynthesis are inhibited by clinically relevant concentrations of β-lactam antibiotics. β-Lactamase production appears to be the major mechanism by whichM. tuberculosis expresses β-lactam resistance. β-Lactamases from the broth supernatant of 3- to 4-week-old cultures of M. tuberculosis H37Ra were partially purified by sequential gel filtration chromatography and chromatofocusing. Three peaks of β-lactamase activity with pI values of 5.1, 4.9, and 4.5, respectively, and which accounted for 10, 78, and 12% of the total postchromatofocusing β-lactamase activity, respectively, were identified. The β-lactamases with pI values of 5.1 and 4.9 were kinetically indistinguishable and exhibited predominant penicillinase activity. In contrast, the β-lactamase with a pI value of 4.5 showed relatively greater cephalosporinase activity. An open reading frame in cosmid Y49 of the DNA library of M. tuberculosis H37Rv with homology to known class A β-lactamases was amplified from chromosomal DNA of M. tuberculosis H37Ra by PCR and was overexpressed in Escherichia coli. The recombinant enzyme was kinetically similar to the pI 5.1 and 4.9 enzymes purified directly from M. tuberculosis. It exhibited predominant penicillinase activity and was especially active against azlocillin. It was inhibited by clavulanic acid andm-aminophenylboronic acid but not by EDTA. We conclude that the major β-lactamase of M. tuberculosis is a class A β-lactamase with predominant penicillinase activity. A second, minor β-lactamase with relatively greater cephalosporinase activity is also present.
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Pestana-Nobles, Roberto, Yani Aranguren-Díaz, Elwi Machado-Sierra, Juvenal Yosa, Nataly J. Galan-Freyle, Laura X. Sepulveda-Montaño, Daniel G. Kuroda, and Leonardo C. Pacheco-Londoño. "Docking and Molecular Dynamic of Microalgae Compounds as Potential Inhibitors of Beta-Lactamase." International Journal of Molecular Sciences 23, no. 3 (January 31, 2022): 1630. http://dx.doi.org/10.3390/ijms23031630.
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Bacterial resistance is responsible for a wide variety of health problems, both in children and adults. The persistence of symptoms and infections are mainly treated with β-lactam antibiotics. The increasing resistance to those antibiotics by bacterial pathogens generated the emergence of extended-spectrum β-lactamases (ESBLs), an actual public health problem. This is due to rapid mutations of bacteria when exposed to antibiotics. In this case, β-lactamases are enzymes used by bacteria to hydrolyze the beta-lactam rings present in the antibiotics. Therefore, it was necessary to explore novel molecules as potential β-lactamases inhibitors to find antibacterial compounds against infection caused by ESBLs. A computational methodology based on molecular docking and molecular dynamic simulations was used to find new microalgae metabolites inhibitors of β-lactamase. Six 3D β-lactamase proteins were selected, and the molecular docking revealed that the metabolites belonging to the same structural families, such as phenylacridine (4-Ph), quercetin (Qn), and cryptophycin (Cryp), exhibit a better binding score and binding energy than commercial clinical medicine β-lactamase inhibitors, such as clavulanic acid, sulbactam, and tazobactam. These results indicate that 4-Ph, Qn, and Cryp molecules, homologous from microalgae metabolites, could be used, likely as novel β-lactamase inhibitors or as structural templates for new in-silico pharmaceutical designs, with the possibility of combatting β-lactam resistance
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Biedenbach, Douglas J., Krystyna Kazmierczak, Samuel K. Bouchillon, Daniel F. Sahm, and Patricia A. Bradford. "In VitroActivity of Aztreonam-Avibactam against a Global Collection of Gram-Negative Pathogens from 2012 and 2013." Antimicrobial Agents and Chemotherapy 59, no. 7 (May 11, 2015): 4239–48. http://dx.doi.org/10.1128/aac.00206-15.
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ABSTRACTThe combination of aztreonam plus avibactam is being developed for use in infections caused by metallo-β-lactamase-producingEnterobacteriaceaestrains that also produce serine β-lactamases. Thein vitroactivities of aztreonam-avibactam and comparator antimicrobials were determined against year 2012 and 2013 clinical isolates ofEnterobacteriaceae,Pseudomonas aeruginosa, andAcinetobacter baumanniiusing the broth microdilution methodology recommended by the Clinical and Laboratory Standards Institute (CLSI). A total of 28,501 unique clinical isolates were obtained from patients in 190 medical centers within 39 countries. MIC90values of aztreonam and aztreonam-avibactam against all collected isolates ofEnterobacteriaceae(n= 23,516) were 64 and 0.12 μg/ml, respectively, with 76.2% of the isolates inhibited by ≤4 μg/ml of aztreonam (the CLSI breakpoint) and 99.9% of the isolates inhibited by ≤4 μg/ml of aztreonam-avibactam using a fixed concentration of 4 μg/ml of avibactam. The MIC90was 32 μg/ml for both aztreonam and aztreonam-avibactam againstP. aeruginosa(n= 3,766). Aztreonam alone or in combination with avibactam had noin vitroactivity against isolates ofA. baumannii. PCR and sequencing were used to characterize 5,076 isolates for β-lactamase genes. Aztreonam was not active against mostEnterobacteriaceaeisolates producing class A or class C enzymes alone or in combination with class B metallo-β-lactamases. In contrast, >99% ofEnterobacteriaceaeisolates producing all observed Ambler classes of β-lactamase enzymes were inhibited by ≤4 μg/ml aztreonam in combination with avibactam, including isolates that produced IMP-, VIM-, and NDM-type metallo-β-lactamases in combination with multiple serine β-lactamases.
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Vilar, Mateja, Moreno Galleni, Tom Solmajer, Boris Turk, Jean-Marie Frère, and André Matagne. "Kinetic Study of Two Novel Enantiomeric Tricyclic β-Lactams Which Efficiently Inactivate Class C β-Lactamases." Antimicrobial Agents and Chemotherapy 45, no. 8 (August 1, 2001): 2215–23. http://dx.doi.org/10.1128/aac.45.8.2215-2223.2001.
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ABSTRACT A detailed kinetic study of the interaction between two ethylidene derivatives of tricyclic carbapenems, Lek 156 and Lek 157, and representative β-lactamases andd-alanyl–d-alanine peptidases (dd-peptidases) is presented. Both compounds are very efficient inactivators of the Enterobacter cloacae 908R β-lactamase, which is usually resistant to inhibition. Preliminary experiments indicate that various extended-spectrum class C β-lactamases (ACT-1, CMY-1, and MIR-1) are also inactivated. With the E. cloacae 908R enzyme, complete inactivation occurs with a second-order rate constant,k 2/K′, of 2 × 104to 4 × 104 M−1 s−1, and reactivation is very slow, with a half-life of >1 h. Accordingly, Lek 157 significantly decreases the MIC of ampicillin for E. cloacae P99, a constitutive class C β-lactamase overproducer. With the other serine β-lactamases tested, the covalent adducts exhibit a wide range of stabilities, with half-lives ranging from long (>4 h with the TEM-1 class A enzyme), to medium (10 to 20 min with the OXA-10 class D enzyme), to short (0.2 to 0.4 s with the NmcA class A β-lactamase). By contrast, both carbapenems behave as good substrates of the Bacillus cereus metallo-β-lactamase (class B). TheStreptomyces sp. strain R61 and K15 extracellulardd-peptidases exhibit low levels of sensitivity to both compounds.
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Matsumoto, Yoshimi, and Matsuhisa Inoue. "Characterization of SFO-1, a Plasmid-Mediated Inducible Class A β-Lactamase from Enterobacter cloacae." Antimicrobial Agents and Chemotherapy 43, no. 2 (February 1, 1999): 307–13. http://dx.doi.org/10.1128/aac.43.2.307.
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ABSTRACT Enterobacter cloacae 8009 produced an inducible class A β-lactamase which hydrolyzed cefotaxime efficiently. It also hydrolyzed other β-lactams except cephamycins and carbapenems. The activity was inhibited by clavulanic acid and imipenem. Thebla gene was transferable to Escherichia coliby electroporation of plasmid DNA. The molecular mass of the β-lactamase was 29 kDa and its pI was 7.3. All of these phenotypic characteristics of the enzyme except for inducible production resemble those of some extended-spectrum class A β-lactamases like FEC-1. The gene encoding this β-lactamase was cloned and sequenced. The deduced amino acid sequence of the β-lactamase was homologous to the AmpA sequences of the Serratia fonticola chromosomal enzyme (96%), MEN-1 (78%), Klebsiella oxytoca chromosomal enzymes (77%), TOHO-1 (75%), and FEC-1 (72%). The conserved sequences of class A β-lactamases, including the S-X(T)-X(S)-K motif, in the active site were all conserved in this enzyme. On the basis of the high degree of homology to the β-lactamase of S. fonticola, the enzyme was named SFO-1. The ampR gene was located upstream of the ampA gene, and the AmpR sequence of SFO-1 had homology with the AmpR sequences of the chromosomal β-lactamases from Citrobacter diversus(80%), Proteus vulgaris (68%), and Pseudomonas aeruginosa (60%). SFO-1 was also inducible in E. coli. However, a transformant harboring plasmid without intactampR produced a small amount of β-lactamase constitutively, suggesting that AmpR works as an activator ofampA of SFO-1. This is the first report from Japan describing an inducible plasmid-mediated class A β-lactamase in gram-negative bacteria.
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Bethel, Christopher R., Andrea M. Hujer, Kristine M. Hujer, Jodi M. Thomson, Mark W. Ruszczycky, Vernon E. Anderson, Marianne Pusztai-Carey, Magdalena Taracila, Marion S. Helfand, and Robert A. Bonomo. "Role of Asp104 in the SHV β-Lactamase." Antimicrobial Agents and Chemotherapy 50, no. 12 (September 18, 2006): 4124–31. http://dx.doi.org/10.1128/aac.00848-06.
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ABSTRACT Among the TEM-type extended-spectrum β-lactamases (ESBLs), an amino acid change at Ambler position 104 (Glu to Lys) results in increased resistance to ceftazidime and cefotaxime when found with other substitutions (e.g., Gly238Ser and Arg164Ser). To examine the role of Asp104 in SHV β-lactamases, site saturation mutagenesis was performed. Our goal was to investigate the properties of amino acid residues at this position that affect resistance to penicillins and oxyimino-cephalosporins. Unexpectedly, 58% of amino acid variants at position 104 in SHV expressed in Escherichia coli DH10B resulted in β-lactamases with lowered resistance to ampicillin. In contrast, increased resistance to cefotaxime was demonstrated only for the Asp104Arg and Asp104Lys β-lactamases. When all 19 substitutions were introduced into the SHV-2 (Gly238Ser) ESBL, the most significant increases in cefotaxime and ceftazidime resistance were noted for both the doubly substituted Asp104Lys Gly238Ser and the doubly substituted Asp104Arg Gly238Ser β-lactamases. Correspondingly, the overall catalytic efficiency (k cat/Km ) of hydrolysis for cefotaxime was increased from 0.60 ± 0.07 μM−1 s−1 (mean ± standard deviation) for Gly238Ser to 1.70 ± 0.01 μM−1 s−1 for the Asp104Lys and Gly238Ser β-lactamase (threefold increase). We also showed that (i) k 3 was the rate-limiting step for the hydrolysis of cefotaxime by Asp104Lys, (ii) the Km for cefotaxime of the doubly substituted Asp104Lys Gly238Ser variant approached that of the Gly238Ser β-lactamase as pH increased, and (iii) Lys at position 104 functions in an energetically additive manner with the Gly238Ser substitution to enhance catalysis of cephalothin. Based on this analysis, we propose that the amino acid at Ambler position 104 in SHV-1 β-lactamase plays a major role in substrate binding and recognition of oxyimino-cephalosporins and influences the interactions of Tyr105 with penicillins.
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Drawz, Sarah M., Christopher R. Bethel, Venkata R. Doppalapudi, Anjaneyulu Sheri, Sundar Ram Reddy Pagadala, Andrea M. Hujer, Marion J. Skalweit, et al. "Penicillin Sulfone Inhibitors of Class D β-Lactamases." Antimicrobial Agents and Chemotherapy 54, no. 4 (January 19, 2010): 1414–24. http://dx.doi.org/10.1128/aac.00743-09.
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ABSTRACT OXA β-lactamases are largely responsible for β-lactam resistance in Acinetobacter spp. and Pseudomonas aeruginosa, two of the most difficult-to-treat nosocomial pathogens. In general, the β-lactamase inhibitors used in clinical practice (clavulanic acid, sulbactam, and tazobactam) demonstrate poor activity against class D β-lactamases. To overcome this challenge, we explored the abilities of β-lactamase inhibitors of the C-2- and C-3-substituted penicillin and cephalosporin sulfone families against OXA-1, extended-spectrum (OXA-10, OXA-14, and OXA-17), and carbapenemase-type (OXA-24/40) class D β-lactamases. Three C-2-substituted penicillin sulfone compounds (JDB/LN-1-255, JDB/LN-III-26, and JDB/ASR-II-292) showed low Ki values for the OXA-1 β-lactamase (0.70 ± 0.14 → 1.60 ± 0.30 μM) and demonstrated significant Ki improvements compared to the C-3-substituted cephalosporin sulfone (JDB/DVR-II-214), tazobactam, and clavulanic acid. The C-2-substituted penicillin sulfones JDB/ASR-II-292 and JDB/LN-1-255 also demonstrated low Ki s for the OXA-10, -14, -17, and -24/40 β-lactamases (0.20 ± 0.04 → 17 ± 4 μM). Furthermore, JDB/LN-1-255 displayed stoichiometric inactivation of OXA-1 (the turnover number, i.e., the partitioning of the initial enzyme inhibitor complex between hydrolysis and enzyme inactivation [tn ] = 0) and tn s ranging from 5 to 8 for the other OXA enzymes. Using mass spectroscopy to study the intermediates in the inactivation pathway, we determined that JDB/LN-1-255 inhibited OXA β-lactamases by forming covalent adducts that do not fragment. On the basis of the substrate and inhibitor kinetics of OXA-1, we constructed a model showing that the C-3 carboxylate of JDB/LN-1-255 interacts with Ser115 and Thr213, the R-2 group at C-2 fits between the space created by the long B9 and B10 β strands, and stabilizing hydrophobic interactions are formed between the pyridyl ring of JDB/LN-1-255 and Val116 and Leu161. By exploiting conserved structural and mechanistic features, JDB/LN-1-255 is a promising lead compound in the quest for effective inhibitors of OXA-type β-lactamases.
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Gorbacheva, A. Yu, and M. L. Maksimov. "Use of amoxicillin/sulbactam/trifamox in acute bacterial sinusitis." Glavvrač (Chief Medical Officer), no. 7 (July 1, 2022): 14–16. http://dx.doi.org/10.33920/med-03-2207-03.
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The most common mechanism of bacterial resistance accounting for about 80% of all cases is the enzymatic cleavage of the antibiotic. Enzymes that destroy β-lactam antibiotics are called β-lactamases. They destroy the amide bond in the β-lactam ring of β-lactam antibiotics, which manifests itself as the absence of the result of the action of antibiotics. The use of β-lactamase inhibitors (clavulanic acid, sulbactam and tazobactam) allows maintaining the benefits of long-known efficient antibiotics. Based on the β-lactam structure, they have a high affinity for β-lactamases and, as a result of a complex physicochemical process, form stable inactive complexes with these enzymes (β-lactamases suicide inhibitor). Under the influence of β-lactamases produced by bacteria, they are not hydrolyzed, like amoxicillin, but are firmly bound to them, protecting amoxicillin from hydrolysis. The use of Trifamox in modern antibiotic therapy is relevant not only in the hospital, but also on an outpatient basis, with recurrent diseases that are not amenable to treatment with conventional β-lactams.
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Beshnova, D. A., C. Carolan, V. G. Grigorenko, M. Yu Rubtsova, E. Gbekor, J. Lewis, V. S. Lamzin, and A. M. Egorov. "Scaffold hopping computational approach for searching novel β-lactamase inhibitors." Biomeditsinskaya Khimiya 65, no. 6 (2019): 468–76. http://dx.doi.org/10.18097/pbmc20196506468.
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We present a novel computational ligand-based virtual screening approach with scaffold hopping capabilities for the identification of novel inhibitors of β-lactamases which confer bacterial resistance to β-lactam antibiotics. The structures of known β-lactamase inhibitors were used as query ligands, and a virtual in silico screening a database of 8 million drug-like compounds was performed in order to select the ligands with similar shape and charge distribution. A set of numerical descriptors was used such as chirality, eigen spectrum of matrices of interatomic distances and connectivity together with higher order moment invariants that showed their efficiency in the field of pattern recognition but have not yet been employed in drug discovery. The developed scaffold-hopping approach was applied for the discovery of analogues of four allosteric inhibitors of serine β-lactamases. After a virtual in silico screening, the effect of two selected ligands on the activity of TEM type β-lactamase was studied experimentally. New non-β-lactam inhibitors were found that showed more effective inhibition of β-lactamases compared to query ligands.
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Walsh, Timothy R., Mark A. Toleman, Laurent Poirel, and Patrice Nordmann. "Metallo-β-Lactamases: the Quiet before the Storm?" Clinical Microbiology Reviews 18, no. 2 (April 2005): 306–25. http://dx.doi.org/10.1128/cmr.18.2.306-325.2005.
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SUMMARY The ascendancy of metallo-β-lactamases within the clinical sector, while not ubiquitous, has nonetheless been dramatic; some reports indicate that nearly 30% of imipenem-resistant Pseudomonas aeruginosa strains possess a metallo-β-lactamase. Acquisition of a metallo-β-lactamase gene will invariably mediate broad-spectrum β-lactam resistance in P. aeruginosa, but the level of in vitro resistance in Acinetobacter spp. and Enterobacteriaceae is less dependable. Their clinical significance is further embellished by their ability to hydrolyze all β-lactams and by the fact that there is currently no clinical inhibitor, nor is there likely to be for the foreseeable future. The genes encoding metallo-β-lactamases are often procured by class 1 (sometimes class 3) integrons, which, in turn, are embedded in transposons, resulting in a highly transmissible genetic apparatus. Moreover, other gene cassettes within the integrons often confer resistance to aminoglycosides, precluding their use as an alternative treatment. Thus far, the metallo-β-lactamases encoded on transferable genes include IMP, VIM, SPM, and GIM and have been reported from 28 countries. Their rapid dissemination is worrisome and necessitates the implementation of not just surveillance studies but also metallo-β-lactamase inhibitor studies securing the longevity of important anti-infectives.