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Journal of Molecular Biology Aug 2019The β-lactams retain a central place in the antibacterial armamentarium. In Gram-negative bacteria, β-lactamase enzymes that hydrolyze the amide bond of the... (Review)
Review
The β-lactams retain a central place in the antibacterial armamentarium. In Gram-negative bacteria, β-lactamase enzymes that hydrolyze the amide bond of the four-membered β-lactam ring are the primary resistance mechanism, with multiple enzymes disseminating on mobile genetic elements across opportunistic pathogens such as Enterobacteriaceae (e.g., Escherichia coli) and non-fermenting organisms (e.g., Pseudomonas aeruginosa). β-Lactamases divide into four classes; the active-site serine β-lactamases (classes A, C and D) and the zinc-dependent or metallo-β-lactamases (MBLs; class B). Here we review recent advances in mechanistic understanding of each class, focusing upon how growing numbers of crystal structures, in particular for β-lactam complexes, and methods such as neutron diffraction and molecular simulations, have improved understanding of the biochemistry of β-lactam breakdown. A second focus is β-lactamase interactions with carbapenems, as carbapenem-resistant bacteria are of grave clinical concern and carbapenem-hydrolyzing enzymes such as KPC (class A) NDM (class B) and OXA-48 (class D) are proliferating worldwide. An overview is provided of the changing landscape of β-lactamase inhibitors, exemplified by the introduction to the clinic of combinations of β-lactams with diazabicyclooctanone and cyclic boronate serine β-lactamase inhibitors, and of progress and strategies toward clinically useful MBL inhibitors. Despite the long history of β-lactamase research, we contend that issues including continuing unresolved questions around mechanism; opportunities afforded by new technologies such as serial femtosecond crystallography; the need for new inhibitors, particularly for MBLs; the likely impact of new β-lactam:inhibitor combinations and the continuing clinical importance of β-lactams mean that this remains a rewarding research area.
Topics: Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Catalytic Domain; Drug Combinations; Drug Resistance, Bacterial; Enterobacteriaceae; Gram-Negative Bacteria; Humans; Interspersed Repetitive Sequences; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams
PubMed: 30959050
DOI: 10.1016/j.jmb.2019.04.002 -
Microbiology (Reading, England) Aug 2022The discovery of penicillin by Alexander Fleming marked a new era for modern medicine, allowing not only the treatment of infectious diseases, but also the safe... (Review)
Review
The discovery of penicillin by Alexander Fleming marked a new era for modern medicine, allowing not only the treatment of infectious diseases, but also the safe performance of life-saving interventions, like surgery and chemotherapy. Unfortunately, resistance against penicillin, as well as more complex β-lactam antibiotics, has rapidly emerged since the introduction of these drugs in the clinic, and is largely driven by a single type of extra-cytoplasmic proteins, hydrolytic enzymes called β-lactamases. While the structures, biochemistry and epidemiology of these resistance determinants have been extensively characterized, their biogenesis, a complex process including multiple steps and involving several fundamental biochemical pathways, is rarely discussed. In this review, we provide a comprehensive overview of the journey of β-lactamases, from the moment they exit the ribosomal channel until they reach their final cellular destination as folded and active enzymes.
Topics: Anti-Bacterial Agents; Penicillins; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 35943884
DOI: 10.1099/mic.0.001217 -
Antimicrobial Agents and Chemotherapy Apr 2006
Review
Topics: Terminology as Topic; beta-Lactamases
PubMed: 16569819
DOI: 10.1128/AAC.50.4.1123-1129.2006 -
Mini Reviews in Medicinal Chemistry Nov 2013β-lactamase-mediated resistance to β-lactam antibiotics is an increasing threat to clinical antimicrobial chemotherapy. The combinations of β-lactam antibiotics and... (Review)
Review
β-lactamase-mediated resistance to β-lactam antibiotics is an increasing threat to clinical antimicrobial chemotherapy. The combinations of β-lactam antibiotics and β-lactamase inhibitors (such as sulbactam, tazobactam and clavulanic acid) have been successfully used for overcoming class A β-lactamase-mediated resistance. However, none of the inhibitors effective against class B, C or D β-lactamases are available in the clinic, which alarms an urgent need to discover/design broad-spectrum β-lactamase inhibitors or new β-lactam antibiotics capable of evading bacterial enzymatic inactivation. In recent years, inhibitors targeted to serine β-lactamases have been developed rapidly with a few of them under clinical trials. In contrast, none promising class B β-lactamase (metallo-β-lactamase) inhibitors with good druggability have been discovered, despite the increasing number of active molecules reported. In this review, we summarized the potential β-lactamase inhibitors reported in recent years and updated the current status of β-lactamase inhibitor discovery.
Topics: Amino Acid Sequence; Animals; Drug Discovery; Enzyme Inhibitors; Humans; Molecular Sequence Data; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 23895190
DOI: 10.2174/13895575113139990074 -
Current Medicinal Chemistry 2023β-lactam antibiotics treat bacterial infections very effectively, but overuse and misuse have led to resistance. β-lactamase enzymes hydrolyze β-lactam antibiotics... (Review)
Review
β-lactam antibiotics treat bacterial infections very effectively, but overuse and misuse have led to resistance. β-lactamase enzymes hydrolyze β-lactam antibiotics and are the primary cause of resistance in bacteria. Bacteria evolve and clinically mutate to produce such β -lactamase enzymes, which could hydrolyze newly discovered antibiotics. Therefore, carbapenems are considered to be the last resort for antimicrobial treatment. Further, different inhibitors have been discovered to fight these evolving and mutating β- lactamase enzyme resistance. These inhibitors are given in combination with the β-lactam antibiotics to treat bacterial infections effectively. But in due course of time, it has been observed that bacteria develop resistance against this combination. This is an extensive review that discusses different classes of β-lactamase enzymes, their mechanism of action, and the role of critical structural elements like loops and catalytically relevant mutations. Such mutations and structural modifications result in expanding the spectrum of activity, making these β-lactamase enzymes resistant to the newly discovered β-lactam antibiotics and their inhibitors. Detailed knowledge of such mutations, catalytically relevant structural modifications, related kinetics, and action mechanisms could help develop new inhibitors effectively. Further, a detailed discussion of available inhibitors against each class of β-lactamase enzymes is also present.
Topics: Humans; beta-Lactamases; beta-Lactamase Inhibitors; Anti-Bacterial Agents; Monobactams; Bacteria; Bacterial Infections
PubMed: 35726414
DOI: 10.2174/0929867329666220620165429 -
Nature Reviews. Microbiology Mar 2022
Topics: Anti-Bacterial Agents; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 34921242
DOI: 10.1038/s41579-021-00680-y -
Annals of the New York Academy of... Jan 2013β-Lactam antibiotics are the most commonly used antibacterial agents and growing resistance to these drugs is a concern. Metallo-β-lactamases are a diverse set of... (Review)
Review
β-Lactam antibiotics are the most commonly used antibacterial agents and growing resistance to these drugs is a concern. Metallo-β-lactamases are a diverse set of enzymes that catalyze the hydrolysis of a broad range of β-lactam drugs including carbapenems. This diversity is reflected in the observation that the enzyme mechanisms differ based on whether one or two zincs are bound in the active site that, in turn, is dependent on the subclass of β-lactamase. The dissemination of the genes encoding these enzymes among Gram-negative bacteria has made them an important cause of resistance. In addition, there are currently no clinically available inhibitors to block metallo-β-lactamase action. This review summarizes the numerous studies that have yielded insights into the structure, function, and mechanism of action of these enzymes.
Topics: Catalysis; Catalytic Domain; Metalloendopeptidases; Mutagenesis; Protein Binding; Substrate Specificity; beta-Lactamases
PubMed: 23163348
DOI: 10.1111/j.1749-6632.2012.06796.x -
Medicinal Research Reviews 1983In summary, Table XVI shows the inhibition profiles of representative beta-lactamases from each major class of Richmond and Sykes. Either resistance (R) or sensitivity... (Review)
Review
In summary, Table XVI shows the inhibition profiles of representative beta-lactamases from each major class of Richmond and Sykes. Either resistance (R) or sensitivity (S) is given as a general guide to the type of compounds likely to inhibit each class. Thus the (qualitative) statements regarding the effectiveness of clavulanic acid can be taken to represent those for the penam sulfones and similarly for MM4550 and the other olivanic acids, carpetimycins, PS series, and asparenomycins. This can also be said of cloxacillin and the other aromatic carboxamido penicillins. Compounds are also included which are specifically or particularly inhibitory to certain beta-lactamases.
Topics: Anti-Bacterial Agents; Cephalosporins; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Kinetics; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 6358721
DOI: 10.1002/med.2610030402 -
Current Protein & Peptide Science 2018Antibiotic resistance in gram-negative bacteria has emerged as a major health threat that occurs because these bacteria actively produce β-lactamases responsible for... (Review)
Review
Antibiotic resistance in gram-negative bacteria has emerged as a major health threat that occurs because these bacteria actively produce β-lactamases responsible for the inactivation of β-lactam antibiotics. The first β lactamase was reported in E. coli back in 1940, before the release of the first antibiotic penicillin in clinical settings. Later on, large numbers of β-lactamases have been discovered in Gram-positive, Gram-negative bacteria as well as mycobacteria. Currently, numerous three-dimensional structures of serine and metallo-β-lactamases have been solved. The serine β-lactamases essentially consist of two structural domains (an all α and an α/β domain) and the active site is located at the groove between the two domains. The catalysis of serine β-lactamase proceeds via acylation and deacylation reactions. The three dimensional structure of metallo-β-lactamases displayed a common four layer "αβ/βα" motif, with a central "ββ"- sandwich by Zn2+ ion(s), and two α-helices are located on the either side. The active site of metallo-β-lactamases contain either 1 or 2 Zn2+ ions, which is coordinated to metal ligating amino acids and polarized water molecule(s) necessary for the hydrolysis of β-lactam antibiotics. Keeping the above views in mind, in this review we have shed light on the current knowledge of the structures and mechanisms of catalysis of serine and metallo-β-lactamases. Moreover, mutational studies on β-lactamases highlight the importance of the active site residues and residues in the vicinity to the active site pocket in the catalysis. To combat bacterial infections more effeciently novel inhibitors of β-lactamase in combination with antibiotics have been used which also form the theme of the review.
Topics: Acylation; Anti-Bacterial Agents; Bacterial Proteins; Catalysis; Catalytic Domain; Humans; Hydrolysis; Molecular Structure; Protein Binding; Protein Conformation; Serine; Zinc; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 28745223
DOI: 10.2174/0929866524666170724160623 -
International Journal of Antimicrobial... Aug 1999Penicillin, the first of the beta-lactam antibiotics, was introduced into medical practice in the 1940s. Since then, a large number of different beta-lactams, including... (Review)
Review
Penicillin, the first of the beta-lactam antibiotics, was introduced into medical practice in the 1940s. Since then, a large number of different beta-lactams, including penicillins, cephalosporins, monobactams, and carbapenems, have been developed, all of which are structurally related through the presence of a core beta-lactam ring. Resistance to beta-lactam antibiotics among target pathogens developed early in the history of their use. Of the mechanisms of resistance, the most widespread and most important is the destruction of the beta-lactam ring, which is mediated by beta-lactamases. The fact that these resistance enzymes may be coded on plasmids means that they are mobile within a bacterial community, and that they have spread widely. Resistance to beta-lactams mediated by beta-lactamases can be overcome successfully with the use of beta-lactamase inhibitors. The combination of beta-lactams with beta-lactamase inhibitors restores the activity of the beta-lactams, allowing their continued clinical use. The development of beta-lactamase inhibitors allows clinicians to rely on the well-tolerated, clinically effective beta-lactam antibiotics to treat a variety of bacterial infections.
Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Enzyme Inhibitors; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams
PubMed: 10526867
DOI: 10.1016/s0924-8579(99)00085-0