Journal articles on the topic 'Lactams'
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1
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.
Abstract:
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.
2
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
3
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.
4
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.
5
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.
Abstract:
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.
6
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.
Abstract:
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.
7
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.
8
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.
Abstract:
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.
9
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.
10
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.
Abstract:
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.
11
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.
Abstract:
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.
12
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.
13
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.
Abstract:
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.
14
Tarui, Atsushi, Yukiko Karuo, Kazuyuki Sato, Kentaro Kawai, and Masaaki Omote. "Stereoselective Synthesis of Multisubstituted α-fluoro-β-lactams." Current Organic Chemistry 24, no. 18 (November 18, 2020): 2169–80. http://dx.doi.org/10.2174/1385272824666200221114707.
Abstract:
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.
15
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)
16
Srivastava, Nitin. "Key Role of Ionic Liquids in the Cleaner and Greener Synthesis of Lactams." Research Journal of Chemistry and Environment 26, no. 1 (December 25, 2021): 125–30. http://dx.doi.org/10.25303/2601rjce125130.
Abstract:
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.
17
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.
Abstract:
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.
18
Patel, Twisha S., Vince Marshall, Keith S. Kaye, Aaron Smith, Carol Young, Paul Lephart, and Jason M. Pogue. "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 (October 2019): S583—S584. http://dx.doi.org/10.1093/ofid/ofz360.1464.
Abstract:
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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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.
Abstract:
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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Kadry, Ashraf. "Lacking of efflux mechanism in clinical isolate of Pseudomonas aerupinosa highly resistant to β-Lactams And imimnem." Scientia Pharmaceutica 71, no. 2 (May 4, 2003): 89–100. http://dx.doi.org/10.3797/scipharm.aut-03-10.
Abstract:
In this investigation, the isolate of Pseudomonas aeruginosa from cystic fibrosis was highly resistant to β-lactarns and β-lactamase inhibitors. The resistant determinants of clinical isolate to imipenem, ceftazidime, ceftriaxone and cefepime were conjugally non-transfer. The slow or non-enzymatically mediated breakdown of imipenem and other broad spectrum p-lactams suggest the resistance of P.aeruginosa isolate to these drugs might be attributed to either permeability or efflux. Impaired penetration of imipenem and other p-lactams through the membrane was detected by a diminished expression of outer membrane (OM) proteins of approximate weight of 46 and 39 Kdal, matched to Opr D and OprF, respectively. Efflux resistance mechanism for meropenem and p-lactams has been ruled out since the isolate failed to express outer membrane protein of about 50 Kdal, which is matched to Opr M protein channel. Thus, reduced permeability in the clinical isolate may be the main mechanism conferring resistance against p-lactarns including imipenem.
21
Nagpal, Reshma, Jitender Bhalla, and Shamsher S. Bari. "A Comprehensive Review on C-3 Functionalization of β-Lactams." Current Organic Synthesis 16, no. 1 (February 4, 2019): 3–16. http://dx.doi.org/10.2174/1570179415666181116103341.
Abstract:
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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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 (November 2018): S281. http://dx.doi.org/10.1093/ofid/ofy210.793.
Abstract:
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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Therien, Alex G., Joann L. Huber, Kenneth E. Wilson, Patrick Beaulieu, Alexandre Caron, David Claveau, Kathleen Deschamps, et al. "Broadening the Spectrum of β-Lactam Antibiotics through Inhibition of Signal Peptidase Type I." Antimicrobial Agents and Chemotherapy 56, no. 9 (June 18, 2012): 4662–70. http://dx.doi.org/10.1128/aac.00726-12.
Abstract:
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, no. 1 (January 1, 2011): 23–30. http://dx.doi.org/10.5863/1551-6776-16.1.23.
Abstract:
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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Kidwai, M., P. Sapra, and K. R. Shushan. "Synthetic Strategies and Medicinal Properties of β-Lactams." Current Medicinal Chemistry 6, no. 3 (March 1999): 195–215. http://dx.doi.org/10.2174/0929867306666220208205333.
Abstract:
Abstract: More than five decades since the Discovery of Penicillin, the chemistry and biological activity of -lactams continue to attract the wide spread attention of research workers. Owing to high efficacy and extremely safe toxicological profile, they are agents of choice in the current therapeutic index for the bacterial infectious diseases. Tremendous efforts have been made into synthesis and structural modification of the -lactam nucleus to increase antimicrobial activity and pharmacokinetic performance. These efforts resulted in the development of ampicillin, amoxicillin and a group of cephalosporins as clinically effective therapeutic agents. However the rapid emergence of bacterial strains resistant to most generally used members of this class of compound stimulated research for novel -lactams, stable to P lactamase and possess high potency, broad spectrum of activity both in vitro and in vivo. The mode of action of P-lactams is to inhibit an enzyme 'transpeptidase', penicillin binding proteins, critical in the production of bacterial cell wall.
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Gostev, Vladimir V., O. E. Punchenko, and Sergey V. Sidorenko. "The current view on betalactam resistance in Staphylococcus aureus." Clinical Microbiology and Antimicrobial Chemotherapy 23, no. 4 (2021): 375–87. http://dx.doi.org/10.36488/cmac.2021.4.375-387.
Abstract:
The review presents the current view on the different resistance mechanisms of Staphylococcus aureus to beta-lactams, which are ones of the main antibiotics of choice for the treatment of staphylococcal infections. Currently, there are several mechanisms of resistance such as production of staphylococcal beta-lactamase (blaZ), which provides resistance to penicillins and aminopenicillins. Another one is the presence of an alternative penicillin-binding protein (PBP2a), which is the main marker of methicillinresistant S. aureus (MRSA), virtually providing resistance to all beta-lactams, with the exception of antiMRSA cephalosporins. Mutations in PBP2a contribute to the resistance to ceftaroline and ceftobiprol. Among the MRSA there are few exceptions with regards to the phenotypes called oxacillin-sensitive MRSA (OS-MRSA) which are susceptible to oxacillin despite the presence of the mecA encoding PBP2a. In addition, there are mec-independent pathways of beta-lactam resistance that could be found in S. aureus. In particular, mutations in the gdpP are associated with an increase in the intracellular concentration of c-diAMP messengers that promote resistance to beta-lactams, including anti-MRSA cephalosporins. Mutations in PBP4 or its promoter also contribute to the resistance. The mechanism of resistance to beta-lactams in mec-negative S. aureus (borderline oxacillin-resistant S. aureus, BORSA) is associated with the mutations in PBP1, PBP2, PBP3, and PBP4 or the overexpression of staphylococcal beta-lactamase. This review describes those and other phenotypes, the features of resistance mechanisms, clinical significance, as well as the possibilities for phenotypic detection.
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Tsang, Wing Y., Naveed Ahmed, Karl Hemming, and Michael I. Page. "Competitive endo- and exo-cyclic CN fission in the hydrolysis of N-aroyl β-lactams." Canadian Journal of Chemistry 83, no. 9 (September 1, 2005): 1432–39. http://dx.doi.org/10.1139/v05-153.
Abstract:
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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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.
Abstract:
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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Masuda, Nobuhisa, Naomasa Gotoh, Chie Ishii, Eiko Sakagawa, Satoshi Ohya, and 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, no. 2 (February 1, 1999): 400–402. http://dx.doi.org/10.1128/aac.43.2.400.
Abstract:
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.
30
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 (May 2004): 1454–60. http://dx.doi.org/10.1128/aac.48.5.1454-1460.2004.
Abstract:
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.
31
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.
Abstract:
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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Valtonen, Satu J., Jussi S. Kurittu, and Matti T. Karp. "A Luminescent Escherichia coli Biosensor for the High Throughput Detection of β-Lactams." Journal of Biomolecular Screening 7, no. 2 (April 2002): 127–34. http://dx.doi.org/10.1177/108705710200700205.
Abstract:
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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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.
Abstract:
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.
34
Hamerníková, Michaela, Jaroslav Havlíček, Romana Bláhová, Helena Pospíšilová, Hana Votavová, and Karel Kefurt. "6-Amino-2,6-dideoxy- or -2,3,6-trideoxyhexono-1,6-lactams: Synthesis and Conformation." Collection of Czechoslovak Chemical Communications 69, no. 4 (2004): 867–84. http://dx.doi.org/10.1135/cccc20040867.
Abstract:
6-Amino-2,6-dideoxy-D-ribo-hexono-1,6-lactam (1a), 6-amino-2,6-dideoxy-D-arabino-hexono-1,6-lactam (2a), 6-amino-2,3,6-trideoxy-L-threo-hexono-1,6-lactam (3a) and per-O-acetyl derivatives 1b-3b were synthesized and their seven-membered lactam ring conformation was studied. 1H and 13C NMR spectra of the named lactams, measured at low temperature, always disclosed the presence of both 1,NC4 and 4C1,N conformations in ratios which were affected mainly by the stereochemistry of cyclohexane. There were no CD extremes over 200 nm found in water solutions of the lactams 1a and 2a, probably owing to the symmetry of the C2-C6 parts of their seven-membered rings. These results contrast with those previously found for the lactams having OH or OAc at C2, and support a concept of the directive role of the C2 substituent in conformation equilibrium.
35
Hark-Khan, Raida, and 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, no. 4 (July 1, 1995): 978–86. http://dx.doi.org/10.1093/jaoac/78.4.978.
Abstract:
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.
36
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.
Abstract:
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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Bryan, L. E., A. J. Godfrey, and 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, no. 4 (April 1, 1985): 377–80. http://dx.doi.org/10.1139/m85-072.
Abstract:
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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Krey, Steven C., Jeff Waise, and Lee P. Skrupky. "Confronting the Challenge of Beta-Lactam Allergies: A Quasi-Experimental Study Assessing Impact of Pharmacy-Led Interventions." Journal of Pharmacy Practice 32, no. 2 (November 21, 2017): 139–46. http://dx.doi.org/10.1177/0897190017743154.
Abstract:
Objective: To improve allergy history documentation and increase the use of beta-lactams when appropriate in patients with a reported beta-lactam allergy. Methods: This pre–post study was conducted at a 167-bed tertiary care community hospital and evaluated multidisciplinary interventions on allergy documentation and antibiotic selection. Interventions included education, creation of local practice guidelines, and modified practices for pharmacists and pharmacy technicians. Inpatients with a reported beta-lactam allergy receiving at least 1 antibiotic for >24 hours were included; first admissions were assessed. Primary outcomes were documentation of reaction type and percentage of patients receiving non-beta-lactam therapy. Secondary outcomes included documentation of previously tolerated beta-lactams, modification of non-beta-lactam therapy, discharge antibiotics, and adverse reactions. Results: A total of 179 patients were included, 91 preintervention and 88 postintervention. No significant differences were observed between the before versus after groups in the percentage of patients with documentation of reaction type (90.1% vs 89.8%, P = .940) or the overall percentage of patients receiving non-beta-lactams (86.8% vs 84.1%, P = .605). However, significantly more patients in the after phase had documentation of previously tolerated beta-lactams (8.8% vs 28.4%, P = .001), and among patients receiving a non-beta-lactam, a greater percentage was subsequently switched to a beta-lactam (11.4% vs 25.7%, P = .022). One allergic reaction was documented during the study, which occurred in the before phase. Conclusion: Multidisciplinary education and local guideline implementation led by pharmacists may improve allergy documentation and antibiotic selection in patients with reported beta-lactam allergies.
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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.
Abstract:
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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Story-Roller, Elizabeth, and Gyanu Lamichhane. "803. Overcoming β-Lactam Resistance in Mycobacterium abscessus." Open Forum Infectious Diseases 5, suppl_1 (November 2018): S288. http://dx.doi.org/10.1093/ofid/ofy210.810.
Abstract:
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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Barba, Victor, Cecilia Hernández, Susana Rojas-Lima, Norberto Farfán, and Rosa Santillan. "Preparation of N-aryl-substituted spiro-β-lactams via Staudinger cycloaddition." Canadian Journal of Chemistry 77, no. 12 (December 5, 1999): 2025–32. http://dx.doi.org/10.1139/v99-212.
Abstract:
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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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.
Abstract:
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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Sun, Shuhai, Zhuang Li, Zhixing Ren, and Yu Li. "Multi-Dimensional Elimination of β-Lactams in the Rural Wetland: Molecule Design and Screening for More Antibacterial and Degradable Substitutes." Molecules 27, no. 23 (December 2, 2022): 8434. http://dx.doi.org/10.3390/molecules27238434.
Abstract:
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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Cremniter, Julie, Jean-Luc Mainardi, Nathalie Josseaume, Jean-Charles Quincampoix, Lionel Dubost, Jean-Emmanuel Hugonnet, Arul Marie, Laurent Gutmann, Louis B. Rice, and Michel Arthur. "Novel Mechanism of Resistance to Glycopeptide Antibiotics in Enterococcus faecium." Journal of Biological Chemistry 281, no. 43 (August 29, 2006): 32254–62. http://dx.doi.org/10.1074/jbc.m606920200.
Abstract:
Glycopeptides and β-lactams are the major antibiotics available for the treatment of infections due to Gram-positive bacteria. Emergence of cross-resistance to these drugs by a single mechanism has been considered as unlikely because they inhibit peptidoglycan polymerization by different mechanisms. The glycopeptides bind to the peptidyl-d-Ala4-d-Ala5 extremity of peptidoglycan precursors and block by steric hindrance the essential glycosyltransferase and d,d-transpeptidase activities of the penicillin-binding proteins (PBPs). The β-lactams are structural analogues of d-Ala4-d-Ala5 and act as suicide substrates of the d,d-transpeptidase module of the PBPs. Here we have shown that bypass of the PBPs by the recently described β-lactam-insensitive l,d-transpeptidase from Enterococcus faecium (Ldtfm) can lead to high level resistance to glycopeptides and β-lactams. Cross-resistance was selected by glycopeptides alone or serially by β-lactams and glycopeptides. In the corresponding mutants, UDP-MurNAc-pentapeptide was extensively converted to UDP-MurNAc-tetrapeptide following hydrolysis of d-Ala5, thereby providing the substrate of Ldtfm. Complete elimination of d-Ala5, a residue essential for glycopeptide binding, was possible because Ldtfm uses the energy of the l-Lys3-d-Ala4 peptide bond for cross-link formation in contrast to PBPs, which use the energy of the d-Ala4-d-Ala5 bond. This novel mechanism of glycopeptide resistance was unrelated to the previously identified replacement of d-Ala5 by d-Ser or d-lactate.
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Isoda, Motoyuki, Kazuyuki Sato, Yurika Kunugi, Satsuki Tokonishi, Atsushi Tarui, Masaaki Omote, Hideki Minami, and Akira Ando. "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.
Abstract:
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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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.
Abstract:
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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Gostev, Vladimir, Olga Kalinogorskaya, Ksenia Ivanova, Ekaterina Kalisnikova, Irina Lazareva, Polina Starkova, and Sergey Sidorenko. "In Vitro Selection of High-Level Beta-Lactam Resistance in Methicillin-Susceptible Staphylococcus aureus." Antibiotics 10, no. 6 (May 26, 2021): 637. http://dx.doi.org/10.3390/antibiotics10060637.
Abstract:
Selective pressure of beta-lactams is thought to be responsible for mutation selection in methicillin-susceptible Staphylococcus aureus (MSSA). We used next-generation sequencing to compare the genomes of beta-lactamase-positive (SA0707) and -negative (SA0937) MSSA isolates with their derivatives obtained after selection with oxacillin, ceftaroline, or meropenem. Selection with oxacillin and ceftaroline caused a rapid and significant (6–8 times) increase in the minimum inhibitory concentration (MICs) of oxacillin, penicillin, amoxicillin/clavulanate, and ceftaroline against the derivatives of both isolates, associated with growth impairment. Selection with meropenem caused a limited increase in the MICs of all beta-lactams against both isolates. During the initial stages of selection (after 5–15 passages), mutations were detected only in some reads, which indicated the heterogeneity of the population; however, during the later stages, either the population reversed to the wild type or fixation of the mutation was observed in the entire population. Selection with different beta-lactams caused diverse mutational events, but common mutations were detected in gdpP, all penicillin-binding proteins, cell wall regulators (vraST, graR), and deletions in the promoter region of pbp4. Therefore, the disk diffusion test with cefoxitin does not reveal resistance associated with these mechanisms in some cases, which can lead to the failure of beta-lactam therapy.
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Wachino, Jun-ichi, Yoshihiro Yamaguchi, Shigetarou Mori, Hiromasa Kurosaki, Yoshichika Arakawa, and Keigo Shibayama. "Structural Insights into the Subclass B3 Metallo-β-Lactamase SMB-1 and the Mode of Inhibition by the Common Metallo-β-Lactamase Inhibitor Mercaptoacetate." Antimicrobial Agents and Chemotherapy 57, no. 1 (October 15, 2012): 101–9. http://dx.doi.org/10.1128/aac.01264-12.
Abstract:
ABSTRACTA novel subclass B3 metallo-β-lactamase (MBL), SMB-1, recently identified from aSerratia marcescensclinical isolate, showed a higher hydrolytic activity against a wide range of β-lactams than did the other subclass B3 MBLs, i.e., BJP-1 and FEZ-1, from environmental bacteria. To identify the mechanism underlying the differences in substrate specificity among the subclass B3 MBLs, we determined the structure of SMB-1, using 1.6-Å diffraction data. Consequently, we found that SMB-1 reserves a space in the active site to accommodate β-lactam, even with a bulky R1 side chain, due to a loss of amino acid residues corresponding to F31 and L226 of BJP-1, which protrude into the active site to prevent β-lactam from binding. The protein also possesses a unique amino acid residue, Q157, which probably plays a role in recognition of β-lactams via the hydrogen bond interaction, which is missing in BJP-1 and FEZ-1, whoseKmvalues for β-lactams are particularly high. In addition, we determined the mercaptoacetate (MCR)-complexed SMB-1 structure and revealed the mode of its inhibition by MCR: the thiolate group bridges to two zinc ions (Zn1 and Zn2). One of the carboxylate oxygen atoms of MCR makes contact with Zn2 and Ser221, and the other makes contact with T223 and a water molecule. Our results demonstrate the possibility that MCR could be a potent inhibitor for subclass B3 MBLs and that the screening technique using MCR as an inhibitor would be effective for detecting subclass B3 MBL producers.
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Kaur Mann, Maninderjeet, Rupesh Kumar, and Gaurav Bhargava. "Facially Selective Oxo-Diels-Alder Cycloadditions of α-Dienyl-β-Lactam: An Entry to Pyrano Tethered β-Lactams Bifunctional Hybrids." Oriental Journal Of Chemistry 38, no. 3 (June 30, 2022): 790–95. http://dx.doi.org/10.13005/ojc/380334.
Abstract:
The functionalization of -lactams at C-3 position are useful for the strategic improvement in both the dimensions, namely synthetic utility, as versatile intermediate in organic synthesis and biological potential of these heterocyclic systems. The present manuscript involved the -facial selective synthesis -lactam hybrids employing highly regioselective and diastereoselective oxo-Diels–Alder reactions of diethyl ketomalonate with -dienyl--lactam with stereocentres at its - and - positions. This protocol provided the cycloaddition of - and - stereocentric diene with symmetrical heterodienophiles forming biologically potent regioselective and diastereoselective -lactams substituted pyrano bifunctional hybrids in good yields and -facially selectivity.
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Bayles, Thibault, and Catherine Guillou. "Trifluoroethanol Promoted Castagnoli–Cushman Cycloadditions of Imines with Homophthalic Anhydride." Molecules 27, no. 3 (January 27, 2022): 844. http://dx.doi.org/10.3390/molecules27030844.
Abstract:
Lactams are essential compounds in medicinal chemistry and key intermediates in the synthesis of natural products. The Castagnoli–Cushman reaction (CCR) of homophthalic anhydride with imines is an exciting method for accessing cyclic densely substituted lactam products. Most CCRs need to be catalyzed or heated. Herein, we report a new, efficient, metal and catalyst-free CCR for the synthesis of poly-substituted 3,4-lactams utilizing the unique properties of trifluoroethanol (TFE). This procedure provides high-speed and smooth access to a broad range of densely substituted 3,4-lactams in good yields and a 100% atom-economical fashion.