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1
Li, Lu, Qiyao Wang, Hui Zhang, Minjun Yang, Mazhar I. Khan та 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, № 6 (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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Li, Xian-Zhi, Li Zhang, Ramakrishnan Srikumar та Keith Poole. "β-Lactamase Inhibitors Are Substrates for the Multidrug Efflux Pumps of Pseudomonas aeruginosa". Antimicrobial Agents and Chemotherapy 42, № 2 (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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Medina, Marjorie B., Dana J. Poole та M. Ranae Anderson. "A Screening Method for β-Lactams in Tissues Hydrolyzed with Penicillinase I and Lactamase II". Journal of AOAC INTERNATIONAL 81, № 5 (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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Alves, Américo J. S., Nuno G. Alves, Cátia C. Caratão, et al. "Spiro-Lactams as Novel Antimicrobial Agents." Current Topics in Medicinal Chemistry 20, no. 2 (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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Brilhante, R. S. N., L. G. A. Valente, M. F. G. Rocha та ін. "Sesquiterpene Farnesol Contributes to Increased Susceptibility to β-Lactams in Strains of Burkholderia pseudomallei". Antimicrobial Agents and Chemotherapy 56, № 4 (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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Jacobs, Lian M. C., Patrick Consol та Yu Chen. "Drug Discovery in the Field of β-Lactams: An Academic Perspective". Antibiotics 13, № 1 (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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Glen, Karl A., та Iain L. Lamont. "β-lactam Resistance in Pseudomonas aeruginosa: Current Status, Future Prospects". Pathogens 10, № 12 (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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Sekiguchi, Jun-ichiro, Koji Morita, Tomoe Kitao та ін. "KHM-1, a Novel Plasmid-Mediated Metallo-β-Lactamase from a Citrobacter freundii Clinical Isolate". Antimicrobial Agents and Chemotherapy 52, № 11 (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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Asgarali, Azizah, Keith A. Stubbs, Antonio Oliver, David J. Vocadlo та Brian L. Mark. "Inactivation of the Glycoside Hydrolase NagZ Attenuates Antipseudomonal β-Lactam Resistance in Pseudomonas aeruginosa". Antimicrobial Agents and Chemotherapy 53, № 6 (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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Li, Fu, Li Wan, Tongyang Xiao та ін. "In Vitro Activity of β-Lactams in Combination with β-Lactamase Inhibitors against Mycobacterium tuberculosis Clinical Isolates". BioMed Research International 2018 (2 липня 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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Gangadharappa, Bhavya, Manjunath Dammalli та Sharath Rajashekarappa. "β-Lactams and β-Lactamase Inhibitors: Unlocking their potential to address drug resistance". Research Journal of Biotechnology 16, № 8 (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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Yin, Jianhua, Yiyang Sun, Yinting Mao, Miao Jin та 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, № 6 (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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Tarui, Atsushi, Yukiko Karuo, Kazuyuki Sato, Kentaro Kawai та Masaaki Omote. "Stereoselective Synthesis of Multisubstituted α-fluoro-β-lactams". Current Organic Chemistry 24, № 18 (2020): 2169–80. http://dx.doi.org/10.2174/1385272824666200221114707.
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β-Lactams, found in β -lactam antibiotics, are the structurally distorted cyclic compounds being subjected to nucleophilic acyl substitution reaction. α-Fluorination of β -lactams is a simple and expedient approach to control the reactivity of β-lactam ring toward nucleophilic attack, which would hopefully lead to the new design of future antibiotics. From the viewpoint of obtaining multisubstituted α -fluoro-β-lactams, α -bromo-α- fluoro-β-lactams are considered as key compounds for structure functionalization, including nucleophilic substitution reaction, aldol-type reaction and metal-catalyzed crosscoupling reaction. All the reactions can be conducted smoothly to afford a variety of multisubstituted α-fluoro-β-lactams. During the course of the examination, chiral α,α-difluoro- β-lactams and α -bromo-β-fluoro-α-lactams are successfully obtained, which are considered potent precursors for making stereocontrolled multisubstituted α-fluoro-β-lactams.
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Nagira, Yu, Keiko Yamada, Hayato Okade та ін. "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 (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/ &gt;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 (&gt;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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Sayed, Alaa R. M., Nirav R. Shah, Kari B. Basso та ін. "First Penicillin-Binding Protein Occupancy Patterns for 15 β-Lactams and β-Lactamase Inhibitors in Mycobacterium abscessus". Antimicrobial Agents and Chemotherapy 65, № 1 (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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Papp-Wallace, Krisztina M., Baui Senkfor, Julian Gatta та ін. "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, № 11 (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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Patel, Twisha S., Vince Marshall, Keith S. Kaye та ін. "1600. Susceptibility of β-Lactam-Resistant Pseudomonas aeruginosa to Other β-Lactams: Is There Truly a Lack of Cross-Resistance?" Open Forum Infectious Diseases 6, Supplement_2 (2019): S583—S584. http://dx.doi.org/10.1093/ofid/ofz360.1464.
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Abstract Background Resistance to β-lactams in P. aeruginosa is complex with multiple mechanisms contributing. Since different mechanisms impact different β-lactams to differing degrees, a common dogma is that resistance to one β-lactam does not lead to resistance to others. The purpose of this analysis was to assess the frequency of β-lactam cross-resistance in P. aeruginosa. Methods Unique P. aeruginosa isolated in 2017 at Michigan Medicine were included. Overall, susceptibility (using CLSI breakpoints) and MIC distributions of β-lactams were assessed in all isolates and those with β-lactam resistance. Results 3,836 unique P. aeruginosa isolates were included. Resistance to traditional anti-pseudomonal β-lactams ranged from 15–23%, whereas ceftolozane/tazobactam resistance was 6%. Overall, cross-resistance between β-lactams was common. The table displays select β-lactam MIC distributions for all isolates and in those resistant to ≥1 β-lactam. When resistance of one agent was present susceptibility to other β-lactams was generally <40% with the majority of susceptible isolates having MICs at or near the breakpoint. Ceftolozane/tazobactam provided the best activity in this setting with 65–77% susceptibility. Conclusion Cross-resistance between β-lactams in P. aeruginosa is common. In patients at risk for resistant P. aeruginosa, ceftolozane/tazobactam should be considered for empiric coverage. Disclosures All authors: No reported disclosures.
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Yuan, Qinghui, Lin He та 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, № 10 (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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Nagpal, Reshma, Jitender Bhalla та Shamsher S. Bari. "A Comprehensive Review on C-3 Functionalization of β-Lactams". Current Organic Synthesis 16, № 1 (2019): 3–16. http://dx.doi.org/10.2174/1570179415666181116103341.
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Background:A lot of advancement has been made in the area of β-lactams in recent times. Most of the research is targeted towards the synthesis of novel β-lactams, their functionalization and exploring their biological potential. The C-3 functionalization of β-lactams has continued to attract considerable interest of the scientific community due to their utility as versatile intermediates in organic synthesis and their therapeutic applications. This has led to the significant increase in efforts towards developing efficient and economic strategies for C-3 functionalized β-lactams.Objective:The present review aims to highlight recent advancement made in C-3 functionalization of β-lactams.Conclusion:To summarize, functionalization of β-lactams at C-3 is an essential aspect of β-lactam chemistry in order to improve/modify its synthetic utility as well as biological potential. The C-3 carbocation equivalent method has emerged as an important and convenient strategy for C-3 functionalization of β-lactam heterocycles which provides a wide range of β-lactams viz. 3-alkylated β-lactams, 3-aryl/heteroarylated β-lactams, 3- alkoxylated β-lactams. On the other hand, base mediated functionalization of β-lactams via carbanion intermediate is another useful approach but their scope is limited by the requirement of stringent reaction conditions. In addition to this, organometallic reagent mediated α-alkylation of 3-halo/3-keto-β-lactams also emerged as interesting methods for the synthesis of functionalized β-lactams having good yields and diastereoselectivities.
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Drawz, Sarah M., та Robert A. Bonomo. "Three Decades of β-Lactamase Inhibitors". Clinical Microbiology Reviews 23, № 1 (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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Zhang, Song, Xinyu Liao, Tian Ding та Juhee Ahn. "Role of β-Lactamase Inhibitors as Potentiators in Antimicrobial Chemotherapy Targeting Gram-Negative Bacteria". Antibiotics 13, № 3 (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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Tsang, Wing Y., Naveed Ahmed, Karl Hemming та Michael I. Page. "Competitive endo- and exo-cyclic CN fission in the hydrolysis of N-aroyl β-lactams". Canadian Journal of Chemistry 83, № 9 (2005): 1432–39. http://dx.doi.org/10.1139/v05-153.
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The balance between endo- and exo-cyclic CN fission in the hydrolysis of N-aroyl β-lactams shows that the difference in reactivity between strained β-lactams and their acyclic analogues is minimal. Attack of hydroxide ion occurs preferentially at the exocyclic acyl centre rather than that of the β-lactam during the hydrolysis of N-p-nitrobenzoyl β-lactam. In general, both endo- and exo-cyclic CN bond fission occurs in the alkaline hydrolysis of N-aroyl β-lactams, the ratio of which varies with the aryl substituent. Hence, the Brønsted β-values differ for the two processes: 0.55 for the ring-opening reaction and 1.54 for the exocyclic CN bond fission reaction. For the pH-independent and acid-catalysed hydrolysis of N-benzoyl β-lactam, less than 3% of products are derived from exocyclic CN bond fission. Key words: β-lactams, hydrolysis, linear free energy relationships, strain.
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Therien, Alex G., Joann L. Huber, Kenneth E. Wilson та ін. "Broadening the Spectrum of β-Lactam Antibiotics through Inhibition of Signal Peptidase Type I". Antimicrobial Agents and Chemotherapy 56, № 9 (2012): 4662–70. http://dx.doi.org/10.1128/aac.00726-12.
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ABSTRACTThe resistance of methicillin-resistantStaphylococcus aureus(MRSA) to all β-lactam classes limits treatment options for serious infections involving this organism. Our goal is to discover new agents that restore the activity of β-lactams against MRSA, an approach that has led to the discovery of two classes of natural product antibiotics, a cyclic depsipeptide (krisynomycin) and a lipoglycopeptide (actinocarbasin), which potentiate the activity of imipenem against MRSA strain COL. We report here that these imipenem synergists are inhibitors of the bacterial type I signal peptidase SpsB, a serine protease that is required for the secretion of proteins that are exported through the Sec and Tat systems. A synthetic derivative of actinocarbasin, M131, synergized with imipenem bothin vitroandin vivowith potent efficacy. Thein vitroactivity of M131 extends to clinical isolates of MRSA but not to a methicillin-sensitive strain. Synergy is restricted to β-lactam antibiotics and is not observed with other antibiotic classes. We propose that the SpsB inhibitors synergize with β-lactams by preventing the signal peptidase-mediated secretion of proteins required for β-lactam resistance. Combinations of SpsB inhibitors and β-lactams may expand the utility of these widely prescribed antibiotics to treat MRSA infections, analogous to β-lactamase inhibitors which restored the utility of this antibiotic class for the treatment of resistant Gram-negative infections.
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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, № 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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Fisher, Jed F., та Shahriar Mobashery. "β-Lactams from the Ocean". Marine Drugs 21, № 2 (2023): 86. http://dx.doi.org/10.3390/md21020086.
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The title of this essay is as much a question as it is a statement. The discovery of the β-lactam antibiotics—including penicillins, cephalosporins, and carbapenems—as largely (if not exclusively) secondary metabolites of terrestrial fungi and bacteria, transformed modern medicine. The antibiotic β-lactams inactivate essential enzymes of bacterial cell-wall biosynthesis. Moreover, the ability of the β-lactams to function as enzyme inhibitors is of such great medical value, that inhibitors of the enzymes which degrade hydrolytically the β-lactams, the β-lactamases, have equal value. Given this privileged status for the β-lactam ring, it is therefore a disappointment that the exemplification of this ring in marine secondary metabolites is sparse. It may be that biologically active marine β-lactams are there, and simply have yet to be encountered. In this report, we posit a second explanation: that the value of the β-lactam to secure an ecological advantage in the marine environment might be compromised by its close structural similarity to the β-lactones of quorum sensing. The steric and reactivity similarities between the β-lactams and the β-lactones represent an outside-of-the-box opportunity for correlating new structures and new enzyme targets for the discovery of compelling biological activities.
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Dousa, Khalid M., Barry N. Kreiswirth, Sebastian Kurz, and Robert A. Bonomo. "786. Ceftaroline and Avibactam? Is This a Potential Combination for Mycobacterium abscessus Infection?" Open Forum Infectious Diseases 5, suppl_1 (2018): S281. http://dx.doi.org/10.1093/ofid/ofy210.793.
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Abstract Background Mycobacterium abscessus harbors a β-lactamase enzyme, BlaMab, able to hydrolyze penicillins, most cephalosporins and carbapenems. As of today, management of M. abscessus with β-lactams does not include combination of β-lactamase inhibitors. The potential benefit of combinations of several β-lactams with new diazabicyclooctane (DBO) inhibitors, such as relebactam and avibactam, has not been well studied. Based upon the ability to inhibit BlaMab by highly potent DBO inhibitors, our goal herein was to investigate the efficacy of a novel combination, ceftaroline (CEF) and avibactam (AVI), to restore susceptibility to β-lactam antibiotics and inhibit growth. Methods Minimum inhibitory concentrations (MICs) of CEF with or without AVI were examined using the microdilution method. Results MIC50 and MIC90 of CEF is 8 mg/L; in the presence of 4 μg/mL of AVI, the MICs of CEF decreased to ≤4 mg/L in 31 of 35 cases (table). Conclusion Our results add to the growing evidence of using β-lactams as agents effective against Mycobacterial infections. Inhibition of the hydrolytic activity of (BlaMab) using DBOs such as AVI suggest that this combination should be evaluated in animal and clinical models. Disclosures All authors: No reported disclosures.
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Srivastava, Nitin. "Key Role of Ionic Liquids in the Cleaner and Greener Synthesis of Lactams." Research Journal of Chemistry and Environment 26, no. 1 (2021): 125–30. http://dx.doi.org/10.25303/2601rjce125130.
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The antibiotics like cephalosporin, penicillin etc. contain lactams as the main component. Due to increase in bacterial resistance to antibiotics, there is a need of synthesis of novel β-lactam agents that are stable to β-lactamase and have high potency on broad spectrum. Besides this β-lactams also decrease the cholesterol in blood plasma. They are potent anticancer agents and enzyme inhibiting substances. Ionic liquids have been found to be versatile greener solvents employed for the synthesis of lactams with many other advantages in comparison to traditional media. They are said to be “tailored solvents” whose many properties like solubility, viscosity, refractive index density can be managed as per the requirement of the reaction by tuning the size of atoms involved in the ionic liquids. The review envisages the development of sustainable synthesis of lactams using various ionic liquids and emphasizes the research in this area for the development of better synthetic methods.
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Tribuddharat, Chanwit, Richard A. Moore, Patricia Baker та 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, № 7 (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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Masuda, Nobuhisa, Naomasa Gotoh, Chie Ishii, Eiko Sakagawa, Satoshi Ohya та Takeshi Nishino. "Interplay between Chromosomal β-Lactamase and the MexAB-OprM Efflux System in Intrinsic Resistance to β-Lactams inPseudomonas aeruginosa". Antimicrobial Agents and Chemotherapy 43, № 2 (1999): 400–402. http://dx.doi.org/10.1128/aac.43.2.400.
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ABSTRACT We investigated the role of chromosomal β-lactamase and the MexAB-OprM efflux system in intrinsic resistance to β-lactams inPseudomonas aeruginosa. Determination of the susceptibilities of a series of isogenic mutants with impaired production of the β-lactamase and the efflux system to 16 β-lactams including penicillins, cephems, oxacephems, carbapenems, and a monobactam demonstrated that the intrinsic resistance of P. aeruginosa to most of the β-lactams is due to the interplay of both factors.
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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 (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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Valtonen, Satu J., Jussi S. Kurittu та Matti T. Karp. "A Luminescent Escherichia coli Biosensor for the High Throughput Detection of β-Lactams". Journal of Biomolecular Screening 7, № 2 (2002): 127–34. http://dx.doi.org/10.1177/108705710200700205.
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A group-specific bioluminescent Escherichia coli strain for studying the action of β-lactam antibiotics is described. The strain contains a plasmid, pBlaLux1, in which the luciferase genes from Photorhabdus luminescent are inserted under the control of the β-lactam-responsive element ampR/ampC from Citrobacter freundii. In the presence of β-lactams, the bacterial cells are induced to express the luciferase enzyme and three additional enzymes generating the substrate for the luciferase reaction. This biosensor for β-lactams does not need any substrate or cofactor additions, and the bioluminescence can be measured very sensitively in real time by using a luminometer. Basic parameters affecting the light production and induction in the gram-negative model organism E. coli SNO301/pBlaLux1 by various β-lactams were studied. The dose-response curves were bell shaped, indicating toxic effects for the sensor strain at high concentrations of β-lactams. Various β-lactams had fairly different assay ranges: ampicillin, 0.05-1.0 μg/ml; piperacillin, 0.0025-25 μg/ml; imipenem, 0.0025-0.25 μg/ml; cephapirin, 0.025-2.5 μg/ml; cefoxitin, 0.0025-1.5 μg/ml; and oxacillin, 25-500 μg/ml. Also, the induction coefficients (signal over background noninduced control) varied considerably from 3 to 158 in a 2-hour assay. Different non-β-lactam antibiotics did not cause induction. Because the assay can be automated using microplate technologies, the approach may be suitable for higher throughput analysis of β-lactam action.
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Kimura, Soichiro, Masaji Ishiguro, Yoshikazu Ishii, Jimena Alba, and Keizo Yamaguchi. "Role of a Mutation at Position 167 of CTX-M-19 in Ceftazidime Hydrolysis." Antimicrobial Agents and Chemotherapy 48, no. 5 (2004): 1454–60. http://dx.doi.org/10.1128/aac.48.5.1454-1460.2004.
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ABSTRACT CTX-M-19 is a recently identified ceftazidime-hydrolyzing extended-spectrum β-lactamase, which differs from the majority of CTX-M-type β-lactamases that preferentially hydrolyze cefotaxime but not ceftazidime. To elucidate the mechanism of ceftazidime hydrolysis by CTX-M-19, the β-lactam MICs of a CTX-M-19 producer, and the kinetic parameters of the enzyme were confirmed. We reconfirmed here that CTX-M-19 is also stable at a high enzyme concentration in the presence of bovine serum albumin (20 μg/ml). Under this condition, we obtained more accurate kinetic parameters and determined that cefotaxime (k cat /Km , 1.47 × 106 s−1 M−1), cefoxitin (k cat /Km , 62.2 s−1 M−1), and aztreonam (k cat /Km , 1.34 × 103 s−1 M−1) are good substrates and that imipenem (k +2 /K, 1.20 × 102 s−1 M−1) is a poor substrate. However, CTX-M-18 and CTX-M-19 exhibited too high a Km value (2.7 to 5.6 mM) against ceftazidime to obtain their catalytic activity (k cat). Comparison of the MICs with the catalytic efficiency (k cat /Km ) of these enzymes showed that some β-lactams, including cefotaxime, ceftazidime, and aztreonam showed a similar correlation. Using the previously reported crystal structure of the Toho-1 β-lactamase, which belongs to the CTX-M-type β-lactamase group, we have suggested characteristic interactions between the enzymes and the β-lactams ceftazidime, cefotaxime, and aztreonam by molecular modeling. Aminothiazole-bearing β-lactams require a displacement of the aminothiazole moiety due to a severe steric interaction with the hydroxyl group of Ser167 in CTX-M-19, and the displacement affects the interaction between Ser130 and the acidic group such as carboxylate and sulfonate of β-lactams.
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Hark-Khan, Raida, та William A. Moats. "Identification and Measurement of β-Lactam Antibiotic Residues in Milk: Integration of Screening Kits with Liquid Chromatography". Journal of AOAC INTERNATIONAL 78, № 4 (1995): 978–86. http://dx.doi.org/10.1093/jaoac/78.4.978.
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Abstract A procedure for identifying and quantitating violative β-lactams in milk is described. This procedure integrates β-lactam residue detection kits with the multiresidue automated liquid chromatographic (LC) cleanup method developed in our laboratory. Spiked milk was deproteinized, extracted, and subjected to reversed-phase LC using a gradient program that concentrated the β-lactams. Amoxicillin, ampicillin, cephapirin, ceftiofur, cloxacillin, and penicillin G were, thus, separated into 5 fractions that were subsequently tested for activity by using 4 kits. (3-lactams in the positive fractions were quantitated by analytical LC methods developed in our laboratory. The LC cleanup method separated β-lactam antibiotics from each other and from interferences in the matrix and also concentrated the antibiotics, thus increasing the sensitivity of the kits to the β-lactam antibiotics. The procedure facilitated the task of identifying and measuring the β-lactam antibiotics that may be present in milk samples.
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Muñoz-Muñoz, Lara, José A. Aínsa та Santiago Ramón-García. "Repurposing β-Lactams for the Treatment of Mycobacterium kansasii Infections: An In Vitro Study". Antibiotics 12, № 2 (2023): 335. http://dx.doi.org/10.3390/antibiotics12020335.
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Mycobacterium kansasii (Mkn) causes tuberculosis-like lung infection in both immunocompetent and immunocompromised patients. Current standard therapy against Mkn infection is lengthy and difficult to adhere to. Although β-lactams are the most important class of antibiotics, representing 65% of the global antibiotic market, they have been traditionally dismissed for the treatment of mycobacterial infections, as they were considered inactive against mycobacteria. A renewed interest in β-lactams as antimycobacterial agents has shown their activity against several mycobacterial species, including M. tuberculosis, M. ulcerans or M. abscessus; however, information against Mkn is lacking. In this study, we determined the in vitro activity of several β-lactams against Mkn. A selection of 32 agents including all β-lactam chemical classes (penicillins, cephalosporins, carbapenems and monobactams) with three β-lactamase inhibitors (clavulanate, tazobactam and avibactam) were evaluated against 22 Mkn strains by MIC assays. Penicillins plus clavulanate and first- and third-generation cephalosporins were the most active β-lactams against Mkn. Combinatorial time-kill assays revealed favorable interactions of amoxicillin–clavulanate and cefadroxil with first-line Mkn treatment. Amoxicillin–clavulanate and cefadroxil are oral medications that are readily available, and well tolerated with an excellent safety and pharmacokinetic profile that could constitute a promising alternative option for Mkn therapy.
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De Angelis, Giulia, Paola Del Giacomo, Brunella Posteraro, Maurizio Sanguinetti та Mario Tumbarello. "Molecular Mechanisms, Epidemiology, and Clinical Importance of β-Lactam Resistance in Enterobacteriaceae". International Journal of Molecular Sciences 21, № 14 (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 та ін. "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, № 5 (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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Skoglund, Erik, Henrietta Abodakpi, Rafael Rios, 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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Isoda, Motoyuki, Kazuyuki Sato, Yurika Kunugi, et al. "Rh-Catalyzed reductive Mannich-type reaction and its application towards the synthesis of (±)-ezetimibe." Beilstein Journal of Organic Chemistry 12 (July 27, 2016): 1608–15. http://dx.doi.org/10.3762/bjoc.12.157.
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An effective synthesis for syn-β-lactams was achieved using a Rh-catalyzed reductive Mannich-type reaction. A rhodium–hydride complex (Rh–H) derived from diethylzinc (Et2Zn) and a Rh catalyst was used for the 1,4-reduction of an α,β-unsaturated ester to give a Reformatsky-type reagent, which in turn, reacted with an imine to give the syn-β-lactam. Additionally, the reaction was applied to the synthesis of (±)-ezetimibe, a potent β-lactamic cholesterol absorption inhibitor.
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Bryan, L. E., A. J. Godfrey та T. Schollardt. "Virulence of Pseudomonas aeruginosa strains with mechanisms of microbial persistence for β-lactam and aminoglycoside antibiotics in a mouse infection model". Canadian Journal of Microbiology 31, № 4 (1985): 377–80. http://dx.doi.org/10.1139/m85-072.
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A series of mutations and transductants producing low-level aminoglycoside and β-lactam antibiotic resistance of Pseudomonas aeruginosa have been constructed in an isogenic background. The phenotypes of these mutations are identical to or closely resemble those of clinical isolates of P. aeruginosa associated with therapeutic failure or microbial persistence in the presence of members of one or both groups of drugs. Virulence of the mutants was examined in an infection model using iron–dextran treated mice and bacteria grown in low-iron medium. All β-lactam resistant mutants affecting affinity of penicillin-binding proteins for β-lactams, constitutive β-lactamase, or permeability of β-lactams retained parental levels of virulence. Aminoglycoside-resistant mutants with defective energy generation or transductants with modified lipopolysaccharide showed reduced virulence. Strains with the preceding forms of resistance are likely to account for therapeutic failure or microbial persistence with antibiotic treatment. We propose that mechanisms of low or unstable forms of resistance should be designated mechanisms of persistence to differentiate them from more classical mechanisms of resistance.
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Barba, Victor, Cecilia Hernández, Susana Rojas-Lima, Norberto Farfán та Rosa Santillan. "Preparation of N-aryl-substituted spiro-β-lactams via Staudinger cycloaddition". Canadian Journal of Chemistry 77, № 12 (1999): 2025–32. http://dx.doi.org/10.1139/v99-212.
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The interest in the study of β-lactams continues due to their therapeutic importance as antibiotics. In this work, six spiro-β-lactams (7a-7c, 8a-8c) have been prepared using the [2+2] cycloaddition of isomaleimides to acid chlorides. The heterobicyclic structures obtained have been characterized by mass spectrometry, IR, NMR spectroscopy, and for compounds 7a, 7b, and 8b the X-ray crystallographic study showed a nearly planar arrangement for the β-lactam ring.Key words: β-lactams, azetidinone, isomaleimides, ketenes, X-ray crystallography.
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Story-Roller, Elizabeth, та Gyanu Lamichhane. "803. Overcoming β-Lactam Resistance in Mycobacterium abscessus". Open Forum Infectious Diseases 5, suppl_1 (2018): S288. http://dx.doi.org/10.1093/ofid/ofy210.810.
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Abstract Background Mycobacterium abscessus (Mab) is an environmentally acquired nontuberculous mycobacterium (NTM) that causes severe pulmonary infections in patients with chronic lung disease, such as cystic fibrosis (CF). The incidence of drug-resistant Mab infections in CF patients in the United States is steadily rising, making it increasingly difficult to manage these often chronic and incurable infections. Mab requires two enzyme classes, l,d- and d,d-transpeptidases, to synthesize peptidoglycan (PG); an integral component of the bacterial cell wall. Each enzyme class is uniquely susceptible to different classes of β-lactam antibiotics. We hypothesize that a combination of two β-lactams, each specific for an enzyme class, will optimally inhibit PG synthesis and swiftly kill Mab, with potential to overcome drug-resistance. Methods Paired antibiotic combinations were tested in vitro for synergy against the Mab reference strain ATCC 19977 at 106 CFU/mL, per CLSI guidelines. Combinations included two β-lactams, a β-lactam and a β-lactamase inhibitor, or a β-lactam and a rifamycin. The minimum inhibitory concentration (MIC) of each drug was initially confirmed via broth microdilution assay. A validated checkerboard assay was used to determine the fractional inhibitory concentration index (FICI) for each combination to identify pairs that exhibit synergistic activity against Mab. Results Of the initial 227 combinations screened, 18 pairs exhibited a high level of synergy (FICI ≤ 0.5). Half of these were combinations of two β-lactams. The average reduction in MIC for each drug in combination was at least fourfold, with 8/18 combinations exhibiting reductions greater than eightfold. Although MIC breakpoints against Mab have not been established for all of the antibiotics tested in this study, the MICs of at least seven combinations were within the therapeutic range. Conclusion Comprehensive inhibition of essential enzymes involved in PG synthesis requires more than one β-lactam antibiotic, and this phenomenon is hypothesized to be the basis for observed synergy between β-lactams. Some of the combinations reduced MICs to within therapeutically achievable levels, potentially leading to vital new treatment options against drug-resistant Mab. Disclosures All authors: No reported disclosures.
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Kim, In-Suk, Chang-Seok Ki, Sunjoo Kim, et al. "Diversity of Ampicillin Resistance Genes and Antimicrobial Susceptibility Patterns in Haemophilus influenzae Strains Isolated in Korea." Antimicrobial Agents and Chemotherapy 51, no. 2 (2006): 453–60. http://dx.doi.org/10.1128/aac.00960-06.
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ABSTRACT By Etest determination of the susceptibilities of 229 Haemophilus influenzae strains isolated in Korea to 10 antibiotics, the isolates were found to be antibiotic nonsusceptible in the following order: ampicillin (58.1%), trimethoprim-sulfamethoxazole (52%), cefaclor (41.1%), clarithromycin (25.8%), chloramphenicol (14.0%), amoxicillin-clavulanic acid (13.5%), meropenem (11.7%), cefixime (10.9%), cefuroxime (9.2%), and levofloxacin (1.3%). The prevalences of each resistance class were 23.6% for β-lactamase-negative ampicillin-susceptible (BLNAS) strains; 37.6% for strains with the TEM-1 type β-lactamase gene; 1.3% for strains with the ROB-1 type β-lactamase gene; 29.3% for the β-lactamase-negative ampicillin-resistant (BLNAR) strains with a mutation in the ftsI gene, which encodes PBP 3; and 8.3% for β-lactamase-positive amoxicillin-clavulanate-resistant (BLPACR) strains, which showed both resistance mechanisms (i.e., a β-lactamase gene and a mutation in the ftsI gene). The MIC50s of all β-lactams, including cephem and meropenem agents, for the BLNAR strains were two to three times higher than those for the BLNAS strains. This study confirms that the prevalence of BLNAR and BLPACR strains is relatively high and for the first time confirms the presence of H. influenzae strains carrying bla ROB-1 in Korea. Even though mutations in another gene(s) might be involved in β-lactam resistance, these results suggest that mutations in the ftsI gene are important for the development of resistance to β-lactams in H. influenzae strains in Korea.
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Resman, Fredrik, Mikael Ristovski, Arne Forsgren та ін. "Increase of β-Lactam-Resistant Invasive Haemophilus influenzae in Sweden, 1997 to 2010". Antimicrobial Agents and Chemotherapy 56, № 8 (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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Eiamphungporn, Warawan, Nalini Schaduangrat, Aijaz Malik та Chanin Nantasenamat. "Tackling the Antibiotic Resistance Caused by Class A β-Lactamases through the Use of β-Lactamase Inhibitory Protein". International Journal of Molecular Sciences 19, № 8 (2018): 2222. http://dx.doi.org/10.3390/ijms19082222.
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β-Lactams are the most widely used and effective antibiotics for the treatment of infectious diseases. Unfortunately, bacteria have developed several mechanisms to combat these therapeutic agents. One of the major resistance mechanisms involves the production of β-lactamase that hydrolyzes the β-lactam ring thereby inactivating the drug. To overcome this threat, the small molecule β-lactamase inhibitors (e.g., clavulanic acid, sulbactam and tazobactam) have been used in combination with β-lactams for treatment. However, the bacterial resistance to this kind of combination therapy has evolved recently. Therefore, multiple attempts have been made to discover and develop novel broad-spectrum β-lactamase inhibitors that sufficiently work against β-lactamase producing bacteria. β-lactamase inhibitory proteins (BLIPs) (e.g., BLIP, BLIP-I and BLIP-II) are potential inhibitors that have been found from soil bacterium Streptomyces spp. BLIPs bind and inhibit a wide range of class A β-lactamases from a diverse set of Gram-positive and Gram-negative bacteria, including TEM-1, PC1, SME-1, SHV-1 and KPC-2. To the best of our knowledge, this article represents the first systematic review on β-lactamase inhibitors with a particular focus on BLIPs and their inherent properties that favorably position them as a source of biologically-inspired drugs to combat antimicrobial resistance. Furthermore, an extensive compilation of binding data from β-lactamase–BLIP interaction studies is presented herein. Such information help to provide key insights into the origin of interaction that may be useful for rationally guiding future drug design efforts.
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Moats, William A., Robert D. Romanowski та Marjorie B. Medina. "Identification of β-Lactam Antibiotics in Tissue Samples Containing Unknown Microbial Inhibitors". Journal of AOAC INTERNATIONAL 81, № 6 (1998): 1135–40. http://dx.doi.org/10.1093/jaoac/81.6.1135.
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Abstract Antibiotic residues in animal tissues can be detected by various screening tests based on microbial inhibition. In the 7-plate assay used by the U.S. Department of Agriculture's Food Safety and Inspection Service (FSIS), penicillinase is incorporated into all but one plate to distinguish β-lactam antibiotics from other types. However, β-lactams such as cloxacillin and the cephalosporins are resistant to degradation by penicillinase. They may not be identified as β-lactams by this procedure, and thus, they may be identified as unidentified microbial inhibitors (UMIs). However, these penicillinase resistant compounds can be degraded by other β-lactamases. The present study describes an improved screening protocol to identify β-lactam antibiotics classified as UMIs. A multiresidue liquid chromatographic procedure based on a method for determining β-lactams in milk was also used to identify and quantitate residues. The 2 methods were tested with 24 tissue FSIS samples classified as containing UMIs. Of these, 3 contained penicillin G, including one at a violative level, and 5 contained a metabolite of ceftiofur. The others were negative for β-lactam antibiotics.
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Sun, Shuhai, Zhuang Li, Zhixing Ren та Yu Li. "Multi-Dimensional Elimination of β-Lactams in the Rural Wetland: Molecule Design and Screening for More Antibacterial and Degradable Substitutes". Molecules 27, № 23 (2022): 8434. http://dx.doi.org/10.3390/molecules27238434.
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Restricted economic conditions and limited sewage treatment facilities in rural areas lead to the discharge of small-scale breeding wastewater containing higher values of residual beta-lactam antibiotics (β-lactams), which seriously threatens the aquatic environment. In this paper, molecular docking and a comprehensive method were performed to quantify and fit the source modification for the combined biodegradation of β-lactams. Using penicillin (PNC) as the target molecule, combined with contour maps for substitute modification, a three-dimensional quantitative structure–activity relationship (3D-QSAR) model was constructed for the high-performance combined biodegradation of β-lactams. The selected candidate with better environmental friendliness, functionality, and high performance was screened. By using the homology modeling algorithms, the mutant penicillin-binding proteins (PBPs) of Escherichia coli were constructed to have antibacterial resistance against β-lactams. The molecular docking was applied to obtain the target substitute by analyzing the degree of antibacterial resistance of β-lactam substitute. The combined biodegradation of β-lactams and substitute in the constructed wetland (CW) by different wetland plant root secretions was studied using molecular dynamics simulations. The result showed a 49.28% higher biodegradation of the substitutes than PNC when the combined wetland plant species of Eichhornia crassipes, Phragmites australis, and Canna indica L. were employed.
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Saleh, Ahmed A., та Ahmed A. J. Mahmood. "NEW p-AMINODIPHENYLAMINE AMIDE COMPOUNDS: DESIGN, SYNTHESIS AND ANTI β-lACTAMASES ACTIVITY EVALUATION". Chemical Problems 22, № 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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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 (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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Keshri, Vivek, Eric Chabrière, Lucile Pinault та ін. "Promiscuous Enzyme Activity as a Driver of Allo and Iso Convergent Evolution, Lessons from the β-Lactamases". International Journal of Molecular Sciences 21, № 17 (2020): 6260. http://dx.doi.org/10.3390/ijms21176260.
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The probability of the evolution of a character depends on two factors: the probability of moving from one character state to another character state and the probability of the new character state fixation. The more the evolution of a character is probable, the more the convergent evolution will be witnessed, and consequently, convergent evolution could mean that the convergent character evolution results as a combination of these two factors. We investigated this phenomenon by studying the convergent evolution of biochemical functions. For the investigation we used the case of β-lactamases. β-lactamases hydrolyze β-lactams, which are antimicrobials able to block the DD-peptidases involved in bacterial cell wall synthesis. β-lactamase activity is present in two different superfamilies: the metallo-β-lactamase and the serine β-lactamase. The mechanism used to hydrolyze the β-lactam is different for the two superfamilies. We named this kind of evolution an allo-convergent evolution. We further showed that the β-lactamase activity evolved several times within each superfamily, a convergent evolution type that we named iso-convergent evolution. Both types of convergent evolution can be explained by the two evolutionary mechanisms discussed above. The probability of moving from one state to another is explained by the promiscuous β-lactamase activity present in the ancestral sequences of each superfamily, while the probability of fixation is explained in part by positive selection, as the organisms having β-lactamase activity allows them to resist organisms that secrete β-lactams. Indeed, an organism that has a mutation that increases the β-lactamase activity will be selected, as the organisms having this activity will have an advantage over the others.
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Bush, Karen, та Patricia A. Bradford. "β-Lactams and β-Lactamase Inhibitors: An Overview". Cold Spring Harbor Perspectives in Medicine 6, № 8 (2016): a025247. http://dx.doi.org/10.1101/cshperspect.a025247.
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