Journal articles: 'Lactame'

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. AL-Kaisse, Asmaa A., Amina N. AL-Thwani, and Rabab Q. AL-Segar. "PCR Detection of Some ESBLs (bla) Genes in Pseudomonas aeruginosa Isolated from Burn’s Units in Bagdad Hospitals." Journal of Biotechnology Research Center 9, no. 2 (June 1, 2015): 74–80. http://dx.doi.org/10.24126/jobrc.2015.9.2.439.

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Multi drug resistant (MDR) and Extended Spectrum Beta Lactamase (ESBLs) of Pseudomonas aeruginosawere detected. Pseudomonas aeruginosa is a bacterium responsible for severe infections in burn’s units,plasmid DNA analysis and encoded many types of genes responsible for beta-lactamases. To determine thetype of genes responsible for beta-lactam broad spectrum in P. aeruginosa strains isolated from 100 swabsof burn’s units environment, using a molecular methods (PCR) by primers specific to ESBLs (bla ) genesoxacillin hydrolyzing capabilities OXA-10, OXA-4 and Vietnam Extended-Spectrum β-Lactame VEB-1.The results revealed that 15 strains were isolated from burn units environment. All of 15 (100%) werepositive OXA-10 and only one (6.6%) for OXA-4 while the other gene VEB-1 was found in 6 (40%) isolates.تم

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Sörgel, Fritz, Jürgen Bulitta, and Cornelia Landersdorfer. "Pharmakokinetik und Pharmakodynamik der β-Lactame: Was wir über β-Lactame wissen und was wir wissen möchten." Pharmazie in unserer Zeit 35, no. 5 (September 2006): 438–51. http://dx.doi.org/10.1002/pauz.200600191.

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Wälchli, Rudolf, Stefan Bienz, and Manfred Hesse. "Synthese macrocyclischer Lactame aus Ketonen durch Ringerweiterung." Helvetica Chimica Acta 68, no. 2 (March 27, 1985): 484–92. http://dx.doi.org/10.1002/hlca.19850680222.

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Wagner, Klaus, Georg Rudakoff, and Peter Fröhlich. "Untersuchungen des Assoziationsverhaltens einiger Lactame in unpolaren Lösungsmitteln." Zeitschrift für Chemie 15, no. 7 (September 1, 2010): 272–75. http://dx.doi.org/10.1002/zfch.19750150710.

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Scharplaz, Madlaina. "Beta-Lactame – Als Standardtherapie zur Behandlung einer Pneumonie empfohlen." Praxis 94, no. 41 (2005): 1607–8. http://dx.doi.org/10.1024/0369-8394.94.41.1607.

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Li, Lu, Qiyao Wang, Hui Zhang, Minjun Yang, Mazhar I. Khan, and Xiaohui Zhou. "Sensor histidine kinase is a β-lactam receptor and induces resistance to β-lactam antibiotics." Proceedings of the National Academy of Sciences 113, no. 6 (February 1, 2016): 1648–53. http://dx.doi.org/10.1073/pnas.1520300113.

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β-Lactams disrupt bacterial cell wall synthesis, and these agents are the most widely used antibiotics. One of the principle mechanisms by which bacteria resist the action of β-lactams is by producing β-lactamases, enzymes that degrade β-lactams. In Gram-negative bacteria, production of β-lactamases is often induced in response to the antibiotic-associated damage to the cell wall. Here, we have identified a previously unidentified mechanism that governs β-lactamase production. In the Gram-negative enteric pathogenVibrio parahaemolyticus, we found a histidine kinase/response regulator pair (VbrK/VbrR) that controls expression of a β-lactamase. Mutants lacking either VbrK or VbrR do not produce the β-lactamase and are no longer resistant to β-lactam antibiotics. Notably, VbrK autophosphorylation is activated by β-lactam antibiotics, but not by other lactams. However, single amino acid substitutions in the putative periplasmic binding pocket of VbrK leads its phosphorylation in response to both β-lactam and other lactams, suggesting that this kinase is a β-lactam receptor that can directly detect β-lactam antibiotics instead of detecting the damage to cell wall resulting from β-lactams. In strong support of this idea, we found that purified periplasmic sensor domain of VbrK binds penicillin, and that such binding is critical for VbrK autophosphorylation and β-lactamase production. Direct recognition of β-lactam antibiotics by a histidine kinase receptor may represent an evolutionarily favorable mechanism to defend against β-lactam antibiotics.

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Ambrosi, Horst-Dieter, Annamarie Kunath, and Klaus Jähnisch. "β-Lactame und β-Lactam-Zwischenprodukte, 2. Mitt.: Stereoselektive Synthese voncis-3-Amino-1,4-diphenyl-azetidin-2-on." Archiv der Pharmazie 326, no. 6 (1993): 319–21. http://dx.doi.org/10.1002/ardp.19933260603.

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Leygue, N., C. Picard, P. Tisnes, and L. Cazaux. "Macrocyclisation en series lactone, thiolactone et lactame à motif ethylenedioxy." Tetrahedron 44, no. 18 (January 1988): 5845–56. http://dx.doi.org/10.1016/s0040-4020(01)81441-1.

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Diederich, Michel, and Udo Nubbemeyer. "Synthese optisch aktiver neungliedriger Lactame durch zwitterionische Aza-Claisen-Reaktion." Angewandte Chemie 107, no. 9 (May 2, 1995): 1095–98. http://dx.doi.org/10.1002/ange.19951070916.

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Langhals, Heinz, Reda El-Shishtawy, Petra von Unold, and Maximilian Rauscher. "Methoxyperylene Bisimides and Perylene Lactame Imides: Novel, Red Fluorescent Dyes." Chemistry - A European Journal 12, no. 17 (June 2, 2006): 4642–45. http://dx.doi.org/10.1002/chem.200501439.

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Kraus, Wolfgang, Adolf Klenk, Michael Bokel, and Bernhard Vogler. "Tetranortriterpenoid-Lactame mit insektenfraßhemmender Wirkung ausAzadirachta indica A. Juss (Meliaceae)." Liebigs Annalen der Chemie 1987, no. 4 (April 27, 1987): 337–40. http://dx.doi.org/10.1002/jlac.198719870331.

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Lode, Hartmut M. "Klinische Indikationen für β-Lactame: Anwendungen im ambulanten und stationären Bereich." Pharmazie in unserer Zeit 35, no. 5 (September 2006): 428–31. http://dx.doi.org/10.1002/pauz.200600189.

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Li, Xian-Zhi, Li Zhang, Ramakrishnan Srikumar, and Keith Poole. "β-Lactamase Inhibitors Are Substrates for the Multidrug Efflux Pumps of Pseudomonas aeruginosa." Antimicrobial Agents and Chemotherapy 42, no. 2 (February 1, 1998): 399–403. http://dx.doi.org/10.1128/aac.42.2.399.

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ABSTRACT The MexAB-OprM multidrug efflux system exports a number of antimicrobial compounds, including β-lactams. In an attempt to define more fully the range of antimicrobial compounds exported by this system, and, in particular, to determine whether β-lactamase inhibitors were also accommodated by the MexAB-OprM pump, the influence of pump status (its presence or absence) on the intrinsic antibacterial activities of these compounds and on their abilities to enhance β-lactam susceptibility in intact cells was assessed. MIC determinations clearly demonstrated that all three compounds tested, clavulanate, cloxacillin, and BRL42715, were accommodated by the pump. Moreover, by using β-lactams which were readily hydrolyzed by thePseudomonas aeruginosa class C chromosomal β-lactamase, it was demonstrated that elimination of themexAB-oprM-encoded efflux system greatly enhanced the abilities of cloxacillin and BRL42715 (but not clavulanate) to increase β-lactam susceptibility. With β-lactams which were poorly hydrolyzed, however, the inhibitors failed to enhance β-lactam susceptibility in MexAB-OprM+ strains, although BRL42715 did enhance β-lactam susceptibility in MexAB-OprM−strains, suggesting that even with poorly hydrolyzed β-lactams this inhibitor was effective when it was not subjected to efflux. MexEF-OprN-overexpressing strains, but not MexCD-OprJ-overexpressing strains, also facilitated resistance to β-lactamase inhibitors, indicating that these compounds are also substrates for the MexEF-OprN pump. These data indicate that an ability to inactivate MexAB-OprM (and like efflux systems in other bacteria) will markedly enhance the efficacies of β-lactam–β-lactamase inhibitor combinations in treating bacterial infections.

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Benetskiy, Eduard, Susan Lühr, Marcelo Vilches-Herrera, Detlef Selent, Haijun Jiao, Lutz Domke, Katrin Dyballa, Robert Franke, and Armin Börner. "Rhodium-Catalyzed Nonisomerizing Hydroformylation of Methyl Oleate Applying Lactame-Based Phosphoramidite Ligands." ACS Catalysis 4, no. 7 (June 4, 2014): 2130–36. http://dx.doi.org/10.1021/cs500274n.

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Jentzer, O., P. Vanelle, MP Crozet, J. Maldonado, and M. Barreau. "Nouveaux 5-nitroimidazoles à noyau lactame hautement actifs : préparation et propriétés antibactériennes." European Journal of Medicinal Chemistry 26, no. 7 (October 1991): 687–97. http://dx.doi.org/10.1016/0223-5234(91)90118-7.

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Rück-Braun, Karola. "α,β-ungesättigte γ-Lactame über TiCl4-vermittelte Umsetzungen vinyloger Eisenformyl-Komplexe." Angewandte Chemie 109, no. 5 (March 3, 1997): 526–28. http://dx.doi.org/10.1002/ange.19971090518.

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Medina, Marjorie B., Dana J. Poole, and M. Ranae Anderson. "A Screening Method for β-Lactams in Tissues Hydrolyzed with Penicillinase I and Lactamase II." Journal of AOAC INTERNATIONAL 81, no. 5 (September 1, 1998): 963–72. http://dx.doi.org/10.1093/jaoac/81.5.963.

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Abstract Antibiotic residues above tolerance levels are not allowed in foods derived from farm animals. Microbial inhibition assays are used to screen antibiotics in U.S. regulatory laboratories. We developed a screening approach to classify β-lactams through selective hydrolysis of the β-lactam ring with Penase™ or lactamase II, thereby inactivating the β- lactam activity. Optimum conditions for hydrolysis of β-lactams with Penase and lactamase II were determined. p-Lactams were detected by a microbial inhibition assay and with enzyme-linked immunosorbent assays before and after hydrolysis. β- Lactams (10-100 ppb) were spiked in kidney extracts and hydrolyzed. Results indicate a pattern that tentatively classified the β-lactams into 3 subgroups. Desfuroyl-ceftiofur-cysteine, a major metabolite of ceftiofur, was clearly detected. Penicillin G, ampicillin, amoxicillin, and cloxacillin were distinguishable from cephapirin, ceftiofur metabolite, and high levels of hetacillin. Liver and kidney tissue samples were analyzed with the combined enzyme hydrolysis and screening assays, which tentatively identified the residues. This approach can speed up screening analysis of β-lactam residues prior to identification and quantitation by chromatographic analysis, thus enhancing positive identification of residues to provide a safer food supply

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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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Brilhante, R. S. N., L. G. A. Valente, M. F. G. Rocha, T. J. P. G. Bandeira, R. A. Cordeiro, R. A. C. Lima, J. J. G. Leite, et al. "Sesquiterpene Farnesol Contributes to Increased Susceptibility to β-Lactams in Strains of Burkholderia pseudomallei." Antimicrobial Agents and Chemotherapy 56, no. 4 (January 30, 2012): 2198–200. http://dx.doi.org/10.1128/aac.05885-11.

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ABSTRACTThis study aimed to evaluate thein vitrocombination of farnesol and β-lactams againstBurkholderia pseudomallei. A total of 12 β-lactamase-positive strains were tested according to CLSI standards. All strains were inhibited by farnesol, with MICs ranging from 75 to 150 μM. The combination of this compound with β-lactams resulted in statistically significant β-lactam MIC reduction (P≤ 0.05). This study provides new perspectives for the use of farnesol combined with β-lactam antibiotics against strains ofB. pseudomallei.

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Paul, Lieselotte, Peter Polczynski, and Güunter Hilgetag. "Synthese neuartiger β-Lactame; 8-Oxo-5-oxa-1-aza-bicyclo-[4,2,0]-octane." Zeitschrift für Chemie 8, no. 11 (September 1, 2010): 417. http://dx.doi.org/10.1002/zfch.19680081107.

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Omar, Farghaly, and August W. Frahm. "Asymmetrische reduktive Aminierung von Cycloalkanonen, 10. Mitt.: EPC-Synthesecis-bicyclischer Lactame und Amine." Archiv der Pharmazie 323, no. 11 (1990): 923–28. http://dx.doi.org/10.1002/ardp.19903231109.

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Stover, Kayla R., Katie E. Barber, and Jamie L. Wagner. "Allergic Reactions and Cross-Reactivity Potential with Beta-Lactamase Inhibitors." Pharmacy 7, no. 3 (June 28, 2019): 77. http://dx.doi.org/10.3390/pharmacy7030077.

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Although beta-lactam allergies are an emerging focus of stewardship programs and interventions, less is publicly released regarding allergies to beta-lactamase inhibitors. This review presents and evaluates the data regarding allergic reactions with beta-lactamase inhibitors. Clavulanate, sulbactam, and tazobactam are beta-lactam-based beta-lactamase inhibitors that are combined with several penicillins or cephalosporins in order to preserve antimicrobial activity in the presence of beta-lactamases. Avibactam, relebactam, and vaborbactam are non-beta-lactam beta-lactamase inhibitors that are combined with cephalosporins or carbapenems in order to expand the antimicrobial activity against broader-spectrum beta-lactamases. Case reports document hypersensitivity reactions to clavulanate, sulbactam, and tazobactam, but not to avibactam, relebactam, or vaborbactam. Based on these reports and considering the chemical structures, cross-allergenicity with beta-lactams is likely with sulbactam and tazobactam. Considering the slightly altered beta-lactam structure, cross-allergenicity is less likely with clavulanate, but still possible. It appears that cross-allergenicity between beta-lactam antimicrobials and the newer, non-beta-lactam beta-lactamase inhibitors is unlikely. It is important for clinicians to perform allergy testing to both the beta-lactam and the beta-lactamase inhibitor in order to confirm the specific allergy and reaction type.

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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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Alves, Américo J. S., Nuno G. Alves, Cátia C. Caratão, Margarida I. M. Esteves, Diana Fontinha, Inês Bártolo, Maria I. L. Soares, et al. "Spiro-Lactams as Novel Antimicrobial Agents." Current Topics in Medicinal Chemistry 20, no. 2 (February 19, 2020): 140–52. http://dx.doi.org/10.2174/1568026619666191105110049.

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Introduction: Structural modulation of previously identified lead spiro-β-lactams with antimicrobial activity was carried out. Objective: The main objective of this work was to synthesize and evaluate the biological activity of novel spiro-lactams based on previously identified lead compounds with antimicrobial activity. Methods: The target chiral spiro-γ-lactams were synthesized through 1,3-dipolar cycloaddition reaction of a diazo-γ-lactam with electron-deficient dipolarophiles. In vitro activity against HIV and Plasmodium of a wide range of spiro-β-lactams and spiro-γ-lactams was evaluated. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 µM) were identified. Results: A novel synthetic route to chiral spiro-γ-lactams has been established. The studied β- and γ- lactams were not cytotoxic, and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to new and more potent drugs. Conclusion: The designed structural modulation of biologically active spiro-β-lactams involved the replacement of the four-membered β-lactam ring by a five-membered γ-lactam ring. Although conformational and superimposition computational studies revealed no significant differences between β- and γ- lactam pharmacophoric features, the studied structural modulation did not lead to compounds with a similar biological profile. The observed results suggest that the β-lactamic core is a requirement for the activity against both HIV and Plasmodium.

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Anganova, E. V., A. V. Vetokhina, L. A. Raspopina, E. L. Kichigina, and E. D. Savilov. "STATE OF ANTIBIOTICS RESISTANCE OF KLEBSIELLA PNEUMONIAE." Journal of microbiology epidemiology immunobiology, no. 5 (October 28, 2017): 70–77. http://dx.doi.org/10.36233/0372-9311-2017-5-70-77.

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Klebsiella pneumoniae microorganisms belong to a group of the most prevalent clinically significant pathogens with a high level of antibacterial resistance (ESKAPE). The speed of formation of antibiotics-resistance by K. pneumoniae strains has sharply increased and reached pandemic scale. One of the main clinically significant mechanisms of antimicrobial resistance is (3-lactamase production, the groups being active depending on the region, country' and hospital. Currently, a significant part of nosocomial K. pneumoniae is resistant to penicillins, 11I-IV generation cephalosporins. The growth of resistance of klebsiellae to carbapenems is a serious threat to the healthcare system. First ofall, KPC-, OXA-, NDM-, VIM-, IMP-producing Widespread of carbapenem-resistant klebsiellae gives evidence on the necessity of international collaboration within the framework of antibiotics resistance control. An increase of frequency of obtained resistance of K. pneumoniae to non-(3-lactame antibiotics (fluoroquinolones, aminoglycosides) is noted. Isolates of K. pneumoniae resistant to tygecyclin, colistin are registered. In general, the problem of antibiotics resistance of causative agents of human diseases including K. pneumoniae continues to intensify. This is a serious threat to world public health that requires action in all sectors of the state.

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Zhang, Song, Xinyu Liao, Tian Ding, and Juhee Ahn. "Role of β-Lactamase Inhibitors as Potentiators in Antimicrobial Chemotherapy Targeting Gram-Negative Bacteria." Antibiotics 13, no. 3 (March 15, 2024): 260. http://dx.doi.org/10.3390/antibiotics13030260.

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Since the discovery of penicillin, β-lactam antibiotics have commonly been used to treat bacterial infections. Unfortunately, at the same time, pathogens can develop resistance to β-lactam antibiotics such as penicillins, cephalosporins, monobactams, and carbapenems by producing β-lactamases. Therefore, a combination of β-lactam antibiotics with β-lactamase inhibitors has been a promising approach to controlling β-lactam-resistant bacteria. The discovery of novel β-lactamase inhibitors (BLIs) is essential for effectively treating antibiotic-resistant bacterial infections. Therefore, this review discusses the development of innovative inhibitors meant to enhance the activity of β-lactam antibiotics. Specifically, this review describes the classification and characteristics of different classes of β-lactamases and the synergistic mechanisms of β-lactams and BLIs. In addition, we introduce potential sources of compounds for use as novel BLIs. This provides insights into overcoming current challenges in β-lactamase-producing bacteria and designing effective treatment options in combination with BLIs.

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Bogdanowicz-Szwed, Krystyna, and Malgorzata Krasodomska. "Reaktion von 1-Oxa-4-aza-1,3-butadienen mit Ketenen: Synthese funktionalisierter β-Lactame." Monatshefte fuer Chemie/Chemical Monthly 129, no. 1 (1998): 81. http://dx.doi.org/10.1007/s007060050031.

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Mukhopadhyay, S., and P. Chakrabarti. "Altered permeability and beta-lactam resistance in a mutant of Mycobacterium smegmatis." Antimicrobial Agents and Chemotherapy 41, no. 8 (August 1997): 1721–24. http://dx.doi.org/10.1128/aac.41.8.1721.

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Beta-lactam resistance in mycobacteria results from an interplay between the following: (i) beta-lactamase production, (ii) affinity of the penicillin-binding proteins (PBPs) for the drugs, and (iii) permeation of the drugs. A laboratory mutant of Mycobacterium smegmatis was studied in order to evaluate the roles of these factors in beta-lactam resistance. Mutant M13 was between 7- and 78-fold more resistant than the wild type to cephaloridine, cefoxitin, cefazolin, cefamandole, and cephalothin. Increased beta-lactamase activity toward these antibiotics was not observed in the mutant. The PBP profiles of the wild type and M13 were comparable. However, the affinities of PBP 1 for the beta-lactams tested were lower for the mutant than for the wild type. The permeation of the drugs measured in intact cells was lower for M13 than for the parent strain. The liposome swelling technique, which could be used for cephaloridine, also supported this view. Reduced permeation was not restricted to the beta-lactams alone. Glycine uptake was also lower in M13. Taken together, the results suggest that decreased affinities of PBP 1 for beta-lactams, combined with the decreased permeability of the cell wall of the mutant, lead to the development of high-level acquired beta-lactam resistance.

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Nagira, Yu, Keiko Yamada, Hayato Okade, Nami Senju, Yuko Tsutsumi, Yuji Tabata, and Kazuhiko Kato. "1279. In Vitro Activity of Nacubactam (OP0595) Alone and in Combination with β-Lactams against β-Lactamase-Producing Enterobacterales Isolated in Japan." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S655. http://dx.doi.org/10.1093/ofid/ofaa439.1462.

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Abstract Background Nacubactam (NAC) is a novel serine β-lactamase inhibitor in clinical development, and inhibits Ambler class A, class C, and some class D β-lactamases. In addition, it has penicillin-binding protein (PBP) 2-dependent antibacterial activity and an ‘enhancer’ effect when combined with β-lactams bound to PBP3. This study assessed the in vitro activity of NAC alone and in combination with β-lactams against IMP-type metallo-β-lactamase-producing and ESBL-producing Enterobacterales isolated in Japan. Methods The MICs for the clinical isolates in Japan were determined and time kill studies were performed. IMP and ESBL genes were detected by PCR. The MICs were determined by broth microdilution method following CLSI methodology. β-lactams and NAC were tested as a ratio of 1:1. Time kill profiles were also studied according to CLSI methodology. Results The MIC50/MIC90s of NAC alone against 112 IMP-producing Enterobacterales and 154 ESBL-producing Enterobacterales were 2/ >32 and 2/8 mg/L, respectively. Regarding the MICs of cefepime (FEP)/NAC and aztreonam (ATM)/NAC against IMP-producing isolates, the MIC90s were 2 and 1 mg/L and the MIC ranges were 0.06 - 32 and 0.06 - 4 mg/L, respectively. The MIC90s of FEP/NAC and ATM/NAC against ESBL-producing isolates were 0.5 and 1 mg/L. These MIC90s of β-lactam/NAC against IMP-producing and ESBL-producing isolates were significantly lower than those of β-lactam alone (>128 mg/L). The highest MIC of ATM/NAC against IMP-producing isolates was lower than that of FEP/NAC. In addition, bactericidal activities of β-lactam/NAC were observed at the lower concentration of β-lactam compared to that of β-lactam alone. Conclusion NAC in combination with β-lactams showed excellent in vitro activities against not only ESBL-producing Enterobacterales but also IMP-producing Enterobacterales isolated in Japan. ATM/NAC tended to show higher antimicrobial effect against IMP-producing isolates by the enzyme stability of ATM. These results support the complex activities of NAC which works as a β-lactamase inhibitor, an antibacterial agent and also an enhancer when combined with β-lactams. Furthermore, these will be useful for selecting a partner β-lactam for NAC. Disclosures Yu Nagira, MS, Meiji Seika Pharma Co., Ltd. (Employee) Keiko Yamada, BS, Meiji Seika Pharma Co., Ltd. (Employee) Hayato Okade, Ph.D, Meiji Seika Pharma Co., Ltd. (Employee) Nami Senju, BS, Meiji Seika Pharma Co., Ltd. (Employee) Yuko Tsutsumi, MS, Meiji Seika Pharma Co., Ltd. (Employee) Yuji Tabata, Ph.D, Meiji Seika Pharma Co., Ltd. (Employee)

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Sekiguchi, Jun-ichiro, Koji Morita, Tomoe Kitao, Noboru Watanabe, Mitsuhiro Okazaki, Tohru Miyoshi-Akiyama, Masato Kanamori, and Teruo Kirikae. "KHM-1, a Novel Plasmid-Mediated Metallo-β-Lactamase from a Citrobacter freundii Clinical Isolate." Antimicrobial Agents and Chemotherapy 52, no. 11 (September 2, 2008): 4194–97. http://dx.doi.org/10.1128/aac.01337-07.

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ABSTRACT A novel gene, bla KHM-1, encoding a metallo-β-lactamase, KHM-1, was cloned from a clinical isolate of Citrobacter freundii resistant to most β-lactam antibiotics. Escherichia coli expressing bla KHM-1 was resistant to all broad-spectrum β-lactams except for monobactams and showed reduced susceptibility to carbapenems. Recombinant KHM-1 exhibited EDTA-inhibitable hydrolytic activity against most β-lactams, with an overall preference for cephalosporins.

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Glen, Karl A., and Iain L. Lamont. "β-lactam Resistance in Pseudomonas aeruginosa: Current Status, Future Prospects." Pathogens 10, no. 12 (December 18, 2021): 1638. http://dx.doi.org/10.3390/pathogens10121638.

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Pseudomonas aeruginosa is a major opportunistic pathogen, causing a wide range of acute and chronic infections. β-lactam antibiotics including penicillins, carbapenems, monobactams, and cephalosporins play a key role in the treatment of P. aeruginosa infections. However, a significant number of isolates of these bacteria are resistant to β-lactams, complicating treatment of infections and leading to worse outcomes for patients. In this review, we summarize studies demonstrating the health and economic impacts associated with β-lactam-resistant P. aeruginosa. We then describe how β-lactams bind to and inhibit P. aeruginosa penicillin-binding proteins that are required for synthesis and remodelling of peptidoglycan. Resistance to β-lactams is multifactorial and can involve changes to a key target protein, penicillin-binding protein 3, that is essential for cell division; reduced uptake or increased efflux of β-lactams; degradation of β-lactam antibiotics by increased expression or altered substrate specificity of an AmpC β-lactamase, or by the acquisition of β-lactamases through horizontal gene transfer; and changes to biofilm formation and metabolism. The current understanding of these mechanisms is discussed. Lastly, important knowledge gaps are identified, and possible strategies for enhancing the effectiveness of β-lactam antibiotics in treating P. aeruginosa infections are considered.

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Sayed, Alaa R. M., Nirav R. Shah, Kari B. Basso, Manasi Kamat, Yuanyuan Jiao, Bartolome Moya, Dhruvitkumar S. Sutaria, et al. "First Penicillin-Binding Protein Occupancy Patterns for 15 β-Lactams and β-Lactamase Inhibitors in Mycobacterium abscessus." Antimicrobial Agents and Chemotherapy 65, no. 1 (October 26, 2020): e01956-20. http://dx.doi.org/10.1128/aac.01956-20.

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ABSTRACTMycobacterium abscessus causes serious infections that often require over 18 months of antibiotic combination therapy. There is no standard regimen for the treatment of M. abscessus infections, and the multitude of combinations that have been used clinically have had low success rates and high rates of toxicities. With β-lactam antibiotics being safe, double β-lactam and β-lactam/β-lactamase inhibitor combinations are of interest for improving the treatment of M. abscessus infections and minimizing toxicity. However, a mechanistic approach for building these combinations is lacking since little is known about which penicillin-binding protein (PBP) target receptors are inactivated by different β-lactams in M. abscessus. We determined the preferred PBP targets of 13 β-lactams and 2 β-lactamase inhibitors in two M. abscessus strains and identified PBP sequences by proteomics. The Bocillin FL binding assay was used to determine the β-lactam concentrations that half-maximally inhibited Bocillin binding (50% inhibitory concentrations [IC50s]). Principal component analysis identified four clusters of PBP occupancy patterns. Carbapenems inactivated all PBPs at low concentrations (0.016 to 0.5 mg/liter) (cluster 1). Cephalosporins (cluster 2) inactivated PonA2, PonA1, and PbpA at low (0.031 to 1 mg/liter) (ceftriaxone and cefotaxime) or intermediate (0.35 to 16 mg/liter) (ceftazidime and cefoxitin) concentrations. Sulbactam, aztreonam, carumonam, mecillinam, and avibactam (cluster 3) inactivated the same PBPs as cephalosporins but required higher concentrations. Other penicillins (cluster 4) specifically targeted PbpA at 2 to 16 mg/liter. Carbapenems, ceftriaxone, and cefotaxime were the most promising β-lactams since they inactivated most or all PBPs at clinically relevant concentrations. These first PBP occupancy patterns in M. abscessus provide a mechanistic foundation for selecting and optimizing safe and effective combination therapies with β-lactams.

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Tribuddharat, Chanwit, Richard A. Moore, Patricia Baker, and Donald E. Woods. "Burkholderia pseudomallei Class A β-Lactamase Mutations That Confer Selective Resistance against Ceftazidime or Clavulanic Acid Inhibition." Antimicrobial Agents and Chemotherapy 47, no. 7 (July 2003): 2082–87. http://dx.doi.org/10.1128/aac.47.7.2082-2087.2003.

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ABSTRACT Burkholderia pseudomallei, the causative agent of melioidosis, is inherently resistant to a variety of antibiotics including aminoglycosides, macrolides, polymyxins, and β-lactam antibiotics. Despite resistance to many β-lactams, ceftazidime and β-lactamase inhibitor-β-lactam combinations are commonly used for treatment of melioidosis. Here, we examine the enzyme kinetics of β-lactamase isolated from mutants resistant to ceftazidime and clavulanic acid inhibition and describe specific mutations within conserved motifs of the β-lactamase enzyme which account for these resistance patterns. Sequence analysis of regions flanking the B. pseudomallei penA gene revealed a putative regulator gene located downstream of penA. We have cloned and sequenced the penA gene from B. mallei and found it to be identical to penA from B. pseudomallei.

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Resman, Fredrik, Mikael Ristovski, Arne Forsgren, Bertil Kaijser, Göran Kronvall, Patrik Medstrand, Eva Melander, Inga Odenholt, and Kristian Riesbeck. "Increase of β-Lactam-Resistant Invasive Haemophilus influenzae in Sweden, 1997 to 2010." Antimicrobial Agents and Chemotherapy 56, no. 8 (June 11, 2012): 4408–15. http://dx.doi.org/10.1128/aac.00415-12.

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ABSTRACTThe proportions ofHaemophilus influenzaeresistant to ampicillin and other β-lactam antibiotics have been low in Sweden compared to other countries in the Western world. However, a near-doubled proportion of nasopharyngeal SwedishH. influenzaeisolates with resistance to β-lactams has been observed in the last decade. In the present study, the epidemiology and mechanisms of antimicrobial resistance ofH. influenzaeisolates from blood and cerebrospinal fluid in southern Sweden from 1997 to 2010 (n= 465) were studied. Antimicrobial susceptibility testing was performed using disk diffusion, and isolates with resistance to any tested β-lactam were further analyzed in detail. We identified a significantly increased (P= 0.03) proportion of β-lactam-resistant invasiveH. influenzaeduring the study period, which was mainly attributed to a significant recent increase of β-lactamase-negative β-lactam-resistant isolates (P= 0.04). Furthermore, invasive β-lactamase-negative β-lactam-resistantH. influenzaeisolates from 2007 and onwards were found in higher proportions than the corresponding proportions of nasopharyngeal isolates in a national survey. Multiple-locus sequence typing (MLST) of this group of isolates did not completely separate isolates with different resistance phenotypes. However, one cluster of β-lactamase-negative ampicillin-resistant (BLNAR) isolates was identified, and it included isolates from all geographical areas. A truncated variant of a β-lactamase gene with a promoter deletion,blaTEM-1-PΔ dominated among the β-lactamase-positiveH. influenzaeisolates. Our results show that the proportions of β-lactam-resistant invasiveH. influenzaehave increased in Sweden in the last decade.

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Yin, Jianhua, Yiyang Sun, Yinting Mao, Miao Jin, and Haichun Gao. "PBP1a/LpoA but Not PBP1b/LpoB Are Involved in Regulation of the Major β-Lactamase GeneblaAin Shewanella oneidensis." Antimicrobial Agents and Chemotherapy 59, no. 6 (March 30, 2015): 3357–64. http://dx.doi.org/10.1128/aac.04669-14.

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ABSTRACTβ-Lactamase production is one of the most important strategies for Gram-negative bacteria to combat β-lactam antibiotics. Studies of the regulation of β-lactamase expression have largely been focused on the class C β-lactamase AmpC, whose induction by β-lactams requires LysR-type regulator AmpR and permease AmpG-dependent peptidoglycan recycling intermediates. InShewanella, which is ubiquitous in aquatic environments and is a reservoir for antibiotic resistance, production of the class D β-lactamase BlaA confers bacteria with natural resistance to many β-lactams. Expression of theblaAgene in the genus representativeShewanella oneidensisis distinct from the AmpC paradigm because of the lack of an AmpR homologue and the presence of an additional AmpG-independent regulatory pathway. In this study, using transposon mutagenesis, we identify proteins that are involved inblaAregulation. Inactivation ofmrcAandlpoA, which encode penicillin binding protein 1a (PBP1a) and its lipoprotein cofactor, LpoA, respectively, drastically enhancesblaAexpression in the absence of β-lactams. Although PBP1b and its cognate, LpoB, also exist inS. oneidensis, their roles inblaAinduction are dispensable. We further show that themrcA-mediatedblaAexpression is independent of AmpG.

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Papp-Wallace, Krisztina M., Baui Senkfor, Julian Gatta, Weirui Chai, Magdalena A. Taracila, Veerabahu Shanmugasundaram, Seungil Han, et al. "Early Insights into the Interactions of Different β-Lactam Antibiotics and β-Lactamase Inhibitors against Soluble Forms of Acinetobacter baumannii PBP1a and Acinetobacter sp. PBP3." Antimicrobial Agents and Chemotherapy 56, no. 11 (August 20, 2012): 5687–92. http://dx.doi.org/10.1128/aac.01027-12.

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ABSTRACTAcinetobacter baumanniiis an increasingly problematic pathogen in United States hospitals. Antibiotics that can treatA. baumanniiare becoming more limited. Little is known about the contributions of penicillin binding proteins (PBPs), the target of β-lactam antibiotics, to β-lactam–sulbactam susceptibility and β-lactam resistance inA. baumannii. Decreased expression of PBPs as well as loss of binding of β-lactams to PBPs was previously shown to promote β-lactam resistance inA. baumannii. Using anin vitroassay with a reporter β-lactam, Bocillin, we determined that the 50% inhibitory concentrations (IC50s) for PBP1a fromA. baumanniiand PBP3 fromAcinetobactersp. ranged from 1 to 5 μM for a series of β-lactams. In contrast, PBP3 demonstrated a narrower range of IC50s against β-lactamase inhibitors than PBP1a (ranges, 4 to 5 versus 8 to 144 μM, respectively). A molecular model with ampicillin and sulbactam positioned in the active site of PBP3 reveals that both compounds interact similarly with residues Thr526, Thr528, and Ser390. Accepting that many interactions with cell wall targets are possible with the ampicillin-sulbactam combination, the low IC50s of ampicillin and sulbactam for PBP3 may contribute to understanding why this combination is effective againstA. baumannii. Unraveling the contribution of PBPs to β-lactam susceptibility and resistance brings us one step closer to identifying which PBPs are the best targets for novel β-lactams.

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Li, Fu, Li Wan, Tongyang Xiao, Haican Liu, Yi Jiang, Xiuqin Zhao, Ruibai Wang, and Kanglin Wan. "In Vitro Activity of β-Lactams in Combination with β-Lactamase Inhibitors against Mycobacterium tuberculosis Clinical Isolates." BioMed Research International 2018 (July 2, 2018): 1–8. http://dx.doi.org/10.1155/2018/3579832.

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Objectives. Evaluating the activity of nineteen β-lactams in combination with different β-lactamase inhibitors to determine the most potent combination against Mycobacterium tuberculosis (MTB) in vitro. Methods. Drug activity was examined by drug susceptibility test with 122 clinical isolates from China. Mutations of blaC and drug targets ldtMt1, ldtMt2, dacB2, and crfA were analyzed by nucleotide sequencing. Results. Tebipenem (TBM) in combination with clavulanate (CLA) exhibited the highest anti-TB activity. The MIC of β-lactam antibiotics was reduced most evidently in the presence of CLA, compared to avibactam (AVI) and sulbactam (SUB). Eight polymorphism sites were identified in blaC, which were not associated with β-lactams resistance. Interestingly, one strain carrying G514A mutation in blaC was highly susceptible to β-lactams regardless of the presence of inhibitors. The transpeptidase encoding genes, ldtMt1, ldtMt2, and dacB2, harboured three mutations, two mutations, and one mutation, respectively, but no correlation was found between these mutations and drug resistance. Conclusion. The activity of β-lactams against MTB and different synergetic effect of β-lactamase inhibitors were indicated. TBM/CLA exhibited the most activity and has a great prospect in developing novel anti-TB regimen; however, further clinical research is warranted. Moreover, the resistance to the β-lactam antibiotics might not be conferred by single target mutation in MTB and requires further studies.

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Shilla, Jalalpoor. "Survey beta lactamase production and resistance pattern into beta lactame antibiotics in Bacillus cereus strain isolated from staff hands and hospital environment in Iran." African Journal of Microbiology Research 5, no. 19 (September 23, 2011): 2980–85. http://dx.doi.org/10.5897/ajmr11.515.

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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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Skoglund, Erik, Henrietta Abodakpi, Rafael Rios, Lorena Diaz, Elsa De La Cadena, An Q. Dinh, Javier Ardila, et al. "In Vivo Resistance to Ceftolozane/Tazobactam in Pseudomonas aeruginosa Arising by AmpC- and Non-AmpC-Mediated Pathways." Case Reports in Infectious Diseases 2018 (December 23, 2018): 1–4. http://dx.doi.org/10.1155/2018/9095203.

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Two pairs of ceftolozane/tazobactam susceptible/resistant P. aeruginosa were isolated from 2 patients after exposure to β-lactams. The genetic basis of ceftolozane/tazobactam resistance was evaluated, and β-lactam-resistant mechanisms were assessed by phenotypic assays. Whole genome sequencing identified mutations in AmpC including the mutation (V213A) and a deletion of 7 amino acids (P210–G216) in the Ω-loop. Phenotypic assays showed that ceftolozane/tazobactam resistance in the strain with AmpCV213A variant was associated with increased β-lactamase hydrolysis activity. On the other hand, the deletion of 7 amino acids in the Ω-loop of AmpC did not display enhanced β-lactamase activity. Resistance to ceftolozane/tazobactam in P. aeruginosa is associated with changes in AmpC; however, the apparent loss of β-lactamase activity in AmpC∆7 suggests that non-AmpC mechanisms could play an important role in resistance to β-lactam/β-lactamase inhibitor combinations.

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Asgarali, Azizah, Keith A. Stubbs, Antonio Oliver, David J. Vocadlo, and Brian L. Mark. "Inactivation of the Glycoside Hydrolase NagZ Attenuates Antipseudomonal β-Lactam Resistance in Pseudomonas aeruginosa." Antimicrobial Agents and Chemotherapy 53, no. 6 (March 9, 2009): 2274–82. http://dx.doi.org/10.1128/aac.01617-08.

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ABSTRACT The overproduction of chromosomal AmpC β-lactamase poses a serious challenge to the successful treatment of Pseudomonas aeruginosa infections with β-lactam antibiotics. The induction of ampC expression by β-lactams is mediated by the disruption of peptidoglycan (PG) recycling and the accumulation of cytosolic 1,6-anhydro-N-acetylmuramyl peptides, catabolites of PG recycling that are generated by an N-acetyl-β-d-glucosaminidase encoded by nagZ (PA3005). In the absence of β-lactams, ampC expression is repressed by three AmpD amidases encoded by ampD, ampDh2, and ampDh3, which act to degrade these 1,6-anhydro-N-acetylmuramyl peptide inducer molecules. The inactivation of ampD genes results in the stepwise upregulation of ampC expression and clinical resistance to antipseudomonal β-lactams due to the accumulation of the ampC inducer anhydromuropeptides. To examine the role of NagZ on AmpC-mediated β-lactam resistance in P. aeruginosa, we inactivated nagZ in P. aeruginosa PAO1 and in an isogenic triple ampD null mutant. We show that the inactivation of nagZ represses both the intrinsic β-lactam resistance (up to 4-fold) and the high antipseudomonal β-lactam resistance (up to 16-fold) that is associated with the loss of AmpD activity. We also demonstrate that AmpC-mediated resistance to antipseudomonal β-lactams can be attenuated in PAO1 and in a series of ampD null mutants using a selective small-molecule inhibitor of NagZ. Our results suggest that the blockage of NagZ activity could provide a strategy to enhance the efficacies of β-lactams against P. aeruginosa and other gram-negative organisms that encode inducible chromosomal ampC and to counteract the hyperinduction of ampC that occurs from the selection of ampD null mutations during β-lactam therapy.

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Hussan, Jagir R., Stuart G. Irwin, Brya Mathews, Simon Swift, Dustin L. Williams, and Jillian Cornish. "Optimal dose of lactoferrin reduces the resilience of in vitro Staphylococcus aureus colonies." PLOS ONE 17, no. 8 (August 12, 2022): e0273088. http://dx.doi.org/10.1371/journal.pone.0273088.

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The rise in antibiotic resistance has stimulated research into adjuvants that can improve the efficacy of broad-spectrum antibiotics. Lactoferrin is a candidate adjuvant; it is a multifunctional iron-binding protein with antimicrobial properties. It is known to show dose-dependent antimicrobial activity against Staphylococcus aureus through iron sequestration and repression of β–lactamase expression. However, S. aureus can extract iron from lactoferrin through siderophores for their growth, which confounds the resolution of lactoferrin’s method of action. We measured the minimum inhibitory concentration (MIC) for a range of lactoferrin/ β–lactam antibiotic dose combinations and observed that at low doses (< 0.39 μM), lactoferrin contributes to increased S. aureus growth, but at higher doses (> 6.25 μM), iron-depleted native lactoferrin reduced bacterial growth and reduced the MIC of the β-lactam-antibiotic cefazolin. This differential behaviour points to a bacterial population response to the lactoferrin/ β–lactam dose combination. Here, with the aid of a mathematical model, we show that lactoferrin stratifies the bacterial population, and the resulting population heterogeneity is at the basis of the dose dependent response seen. Further, lactoferrin disables a sub-population from β-lactam-induced production of β-lactamase, which when sufficiently large reduces the population’s ability to recover after being treated by an antibiotic. Our analysis shows that an optimal dose of lactoferrin acts as a suitable adjuvant to eliminate S. aureus colonies using β-lactams, but sub-inhibitory doses of lactoferrin reduces the efficacy of β-lactams.

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De Angelis, Giulia, Paola Del Giacomo, Brunella Posteraro, Maurizio Sanguinetti, and Mario Tumbarello. "Molecular Mechanisms, Epidemiology, and Clinical Importance of β-Lactam Resistance in Enterobacteriaceae." International Journal of Molecular Sciences 21, no. 14 (July 18, 2020): 5090. http://dx.doi.org/10.3390/ijms21145090.

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Despite being members of gut microbiota, Enterobacteriaceae are associated with many severe infections such as bloodstream infections. The β-lactam drugs have been the cornerstone of antibiotic therapy for such infections. However, the overuse of these antibiotics has contributed to select β-lactam-resistant Enterobacteriaceae isolates, so that β-lactam resistance is nowadays a major concern worldwide. The production of enzymes that inactivate β-lactams, mainly extended-spectrum β-lactamases and carbapenemases, can confer multidrug resistance patterns that seriously compromise therapeutic options. Further, β-lactam resistance may result in increases in the drug toxicity, mortality, and healthcare costs associated with Enterobacteriaceae infections. Here, we summarize the updated evidence about the molecular mechanisms and epidemiology of β-lactamase-mediated β-lactam resistance in Enterobacteriaceae, and their potential impact on clinical outcomes of β-lactam-resistant Enterobacteriaceae infections.

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Lagacé-Wiens, P. R. S., F. Tailor, P. Simner, M. DeCorby, J. A. Karlowsky, A. Walkty, D. J. Hoban, and G. G. Zhanel. "Activity of NXL104 in Combination with β-Lactams against Genetically Characterized Escherichia coli and Klebsiella pneumoniae Isolates Producing Class A Extended-Spectrum β-Lactamases and Class C β-Lactamases." Antimicrobial Agents and Chemotherapy 55, no. 5 (February 28, 2011): 2434–37. http://dx.doi.org/10.1128/aac.01722-10.

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ABSTRACTThe novel non-β-lactam β-lactamase inhibitor NXL104, in combination with cefepime, ceftazidime, ceftriaxone, amdinocillin, and meropenem, was tested against 190 extended-spectrum β-lactamase (ESBL)-producingEscherichia coliandKlebsiella pneumoniaeisolates, 94 AmpC-hyperproducingE. coliisolates, and 8 AmpC/ESBL-coexpressingE. coliisolates. NXL104 restored 100% susceptibility to the partner cephalosporins for all isolates tested. Amdinocillin and meropenem MICs were modestly improved (2 to 32 times lower) by NXL104. These results suggest that NXL104 may be useful in combination with β-lactams for the treatment of infections caused by ESBL- and AmpC-producingEnterobacteriaceae.

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Yuan, Qinghui, Lin He, and Hengming Ke. "A Potential Substrate Binding Conformation of β-Lactams and Insight into the Broad Spectrum of NDM-1 Activity." Antimicrobial Agents and Chemotherapy 56, no. 10 (July 23, 2012): 5157–63. http://dx.doi.org/10.1128/aac.05896-11.

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ABSTRACTNew Delhi metallo-β-lactamase 1 (NDM-1) is a key enzyme that the pathogenKlebsiella pneumoniauses to hydrolyze almost all β-lactam antibiotics. It is currently unclear why NDM-1 has a broad spectrum of activity. Docking of the representatives of the β-lactam families into the active site of NDM-1 is reported here. All the β-lactams naturally fit the NDM-1 pocket, implying that NDM-1 can accommodate the substrates without dramatic conformation changes. The docking reveals two major binding modes of the β-lactams, which we tentatively name the S (substrate) and I (inhibitor) conformers. In the S conformers of all the β-lactams, the amide oxygen and the carboxylic group conservatively interact with two zinc ions, while the substitutions on the fused rings show dramatic differences in their conformations and positions. Since the bridging hydroxide ion/water in the S conformer is at the position for the nucleophilic attack, the S conformation may simulate the true binding of a substrate to NDM-1. The I conformer either blocks or displaces the bridging hydroxide ion/water, such as in the case of aztreonam, and is thus inhibitory. The docking also suggests that substitutions on the β-lactam ring are required for β-lactams to bind in the S conformation, and therefore, small β-lactams such as clavulanic acid would be inhibitors of NDM-1. Finally, our docking shows that moxalactam uses its tyrosyl-carboxylic group to compete with the S conformer and would thus be a poor substrate of NDM-1.

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Tajada, P., J. L. Gomez-Graces, J. I. Alós, D. Balas, and R. Cogollos. "Antimicrobial susceptibilities of Campylobacter jejuni and Campylobacter coli to 12 beta-lactam agents and combinations with beta-lactamase inhibitors." Antimicrobial Agents and Chemotherapy 40, no. 8 (August 1996): 1924–25. http://dx.doi.org/10.1128/aac.40.8.1924.

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The in vitro activities of 12 beta-lactam agents against 100 thermophilic Campylobacter strains were tested. Beta-Lactamase production was detected in 88% of all strains tested. Clavulanic acid was the best inhibitor by susceptibility testing. The beta-lactams which displayed high levels of in vitro activity against Campylobacter isolates were imipenem, amoxicillin-clavulanic acid, and cefepime and, to a lesser degree, amoxicillin, ampicillin, and cefotaxime.

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Mahmood, Ahmed A. J., and Safaa P. Bahnam. "DOCKING, SYNTHESIS AND β-LACTAMASE INHIBITORY ACTIVITY EVALUATION FOR NEW AMIDE COMPOUNDS." Chemical Problems 22, no. 2 (2024): 139–49. http://dx.doi.org/10.32737/2221-8688-2024-2-139-149.

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The beta-lactams are recognized as effective antibiotics for treating infections, yet bacterial production of β-lactamase, which hydrolyzes the beta-lactam ring, can render these drugs inactive. Combining these antibiotics with a β-lactamase inhibitor, such as clavulanic acid, mitigates this resistance. In a docking study involving Temoniera-1 (TEM-1), 1pzp, we induced the synthesis of eight amide compounds by reacting acid chloride derivatives with sulphathiazol or oxadiazol amine, forming an amide bond. The newly synthesized compounds were differentiated using physical and spectroscopic methods and verified biologically by estimating their minimum inhibitory concentration (MIC) against four strains of βlactamase G(+)ve and G(-)ve bacteria. Their anti β-lactamase behaviors were then compared with that of clavulanic acid as a co-inhibitor with amoxicillin against the same four strains of bacteria. The results indicate that four of the new amides exhibit excellent anti-β-lactamase activity and contain one or more hydrophobic residues in their structures. Halogen atoms enhance the selectivity of tower β-lactamases. Derivatives of both oxadiazole and sulfathiazole scaffolds show promising anti-β-lactamase activity as nonβ-lactam inhibitors.

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MacDougall, Conan. "Beyond Susceptible and Resistant, Part I: Treatment of Infections Due to Gram-Negative Organisms With Inducible β-Lactamases." Journal of Pediatric Pharmacology and Therapeutics 16, no. 1 (January 1, 2011): 23–30. http://dx.doi.org/10.5863/1551-6776-16.1.23.

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ABSTRACT Inactivation of β-lactams by the action of β-lactamase enzymes is the most common mode of resistance to these drugs among Gram-negative organisms. The genomes of some key clinical pathogens such as Enterobacter and Pseudomonas encode AmpC, an inducible chromosomal β-lactamase. The potent activity of AmpC against broad-spectrum β-lactams complicates treatment of organisms with this gene. Antibiotic exposure can select for mutants expressing high levels of this enzyme, leading to the emergence of resistant isolates and failure of therapy, even when the initial isolate is fully susceptible. The risk of selecting for resistant organisms varies according to the particular β-lactam used for treatment. This article reviews the microbiology of these enzymes, summarizes clinical data on the frequency emergence of resistance, and discusses considerations for antimicrobial treatment of these organisms.

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Saleh, Ahmed A., and Ahmed A. J. Mahmood. "NEW p-AMINODIPHENYLAMINE AMIDE COMPOUNDS: DESIGN, SYNTHESIS AND ANTI β-lACTAMASES ACTIVITY EVALUATION." Chemical Problems 22, no. 1 (2024): 20–32. http://dx.doi.org/10.32737/2221-8688-2024-1-20-32.

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β-Lactams, such as penicillins and cephalosporins, have long been recognized as the most effective antibiotics for the treatment of infectious diseases. However, the major limitation to their effectiveness is the bacterial production of β-lactamase enzymes, which hydrolyze the β-lactam ring in these drugs, rendering them inactive. To overcome this resistance mechanism, β-lactamase inhibitors, such as clavulanic acid, are commonly used in combination with β-lactams. By inhibiting the action of β-lactamase enzymes, these inhibitors restore the efficacy of β-lactam antibiotics. In recent studies, researchers have employed docking techniques to investigate the interaction between β-lactamase enzymes and potential inhibitors. Specifically, the β-lactamases TEM-1 (1pzp) and IMP-1 (1JJE) were used as targets for designing new compounds. A series of novel compounds were generated by synthesizing 6 amides compounds as acid chloride derivatives and reacting them with p-aminodiphenylamine to form amide bonds. These compounds were then characterized by the use of various physical and spectroscopic methods to confirm their structures. Next, the synthesized compounds were subjected to biological testing to evaluate their efficacy against β-lactamaseproducing Gram-positive and Gram-negative bacteria. This was accomplished by determining the minimum inhibitory concentration (MIC) of the compounds against three different strains of bacteria. Additionally, the possible anti β-lactamase activities of the compounds were compared to that of clavulanic acid. The results of this study revealed that five of the synthesized products exhibited effect similar to that of clavulanic acid for only one bacterial strain (Staph. aureus). Furthermore, the findings of the docking study suggest that the β-lactamase active pocket has a preference for hydrophobic substituents, as the synthesized products with these groups showed the highest binding score. In conclusion, the use of β-lactamase inhibitors, such as clavulanic acid, in combination with β-lactam antibiotics has proven effective in combating bacterial resistance. The development of novel compounds with anti β-lactamase activity holds promise for improving the treatment of infectious diseases. By understanding the preferences of the β-lactamase active pocket and designing compounds with hydrophobic substituents, researchers can enhance the affinity and efficacy of these inhibitors. This research contributes to the ongoing efforts to combat antibiotic resistance and improve patient outcomes in the field of infectious disease treatment.

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Garofalo, Barbara, Federica Prati, Rosa Buonfiglio, Isabella Coletta, Noemi D’Atanasio, Angela Molteni, Daniele Carettoni, et al. "Discovery of Novel Chemical Series of OXA-48 β-Lactamase Inhibitors by High-Throughput Screening." Pharmaceuticals 14, no. 7 (June 25, 2021): 612. http://dx.doi.org/10.3390/ph14070612.

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Abstract:

The major cause of bacterial resistance to β-lactams is the production of hydrolytic β-lactamase enzymes. Nowadays, the combination of β-lactam antibiotics with β-lactamase inhibitors (BLIs) is the main strategy for overcoming such issues. Nevertheless, particularly challenging β-lactamases, such as OXA-48, pose the need for novel and effective treatments. Herein, we describe the screening of a proprietary compound collection against Klebsiella pneumoniae OXA-48, leading to the identification of several chemotypes, like the 4-ideneamino-4H-1,2,4-triazole (SC_2) and pyrazolo[3,4-b]pyridine (SC_7) cores as potential inhibitors. Importantly, the most potent representative of the latter series (ID2, AC50 = 0.99 μM) inhibited OXA-48 via a reversible and competitive mechanism of action, as demonstrated by biochemical and X-ray studies; furthermore, it slightly improved imipenem’s activity in Escherichia coli ATCC BAA-2523 β-lactam resistant strain. Also, ID2 showed good solubility and no sign of toxicity up to the highest tested concentration, resulting in a promising starting point for further optimization programs toward novel and effective non-β-lactam BLIs.

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Journal articles on the topic 'Lactame'

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