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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 -
Antimicrobial Agents and Chemotherapy Oct 2018β-Lactamases, the major resistance determinant for β-lactam antibiotics in Gram-negative bacteria, are ancient enzymes whose origins can be traced back millions of... (Review)
Review
β-Lactamases, the major resistance determinant for β-lactam antibiotics in Gram-negative bacteria, are ancient enzymes whose origins can be traced back millions of years ago. These well-studied enzymes, currently numbering almost 2,800 unique proteins, initially emerged from environmental sources, most likely to protect a producing bacterium from attack by naturally occurring β-lactams. Their ancestors were presumably penicillin-binding proteins that share sequence homology with β-lactamases possessing an active-site serine. Metallo-β-lactamases also exist, with one or two catalytically functional zinc ions. Although penicillinases in Gram-positive bacteria were reported shortly after penicillin was introduced clinically, transmissible β-lactamases that could hydrolyze recently approved cephalosporins, monobactams, and carbapenems later became important in Gram-negative pathogens. Nomenclature is based on one of two major systems. Originally, functional classifications were used, based on substrate and inhibitor profiles. A later scheme classifies β-lactamases according to amino acid sequences, resulting in class A, B, C, and D enzymes. A more recent nomenclature combines the molecular and biochemical classifications into 17 functional groups that describe most β-lactamases. Some of the most problematic enzymes in the clinical community include extended-spectrum β-lactamases (ESBLs) and the serine and metallo-carbapenemases, all of which are at least partially addressed with new β-lactamase inhibitor combinations. New enzyme variants continue to be described, partly because of the ease of obtaining sequence data from whole-genome sequencing studies. Often, these new enzymes are devoid of any phenotypic descriptions, making it more difficult for clinicians and antibiotic researchers to address new challenges that may be posed by unusual β-lactamases.
Topics: Bacterial Proteins; Cephalosporins; Gram-Negative Bacteria; Gram-Positive Bacteria; Penicillinase; beta-Lactamases; beta-Lactams
PubMed: 30061284
DOI: 10.1128/AAC.01076-18 -
Antimicrobial Agents and Chemotherapy Sep 2020Modern medicine is threatened by the global rise of antibiotic resistance, especially among Gram-negative bacteria. Metallo-β-lactamase (MBL) enzymes are a particular... (Review)
Review
Modern medicine is threatened by the global rise of antibiotic resistance, especially among Gram-negative bacteria. Metallo-β-lactamase (MBL) enzymes are a particular concern and are increasingly disseminated worldwide, though particularly in Asia. Many MBL producers have multiple further drug resistances, leaving few obvious treatment options. Nonetheless, and more encouragingly, MBLs may be less effective agents of carbapenem resistance , under zinc limitation, than Owing to their unique structure and function and their diversity, MBLs pose a particular challenge for drug development. They evade all recently licensed β-lactam-β-lactamase inhibitor combinations, although several stable agents and inhibitor combinations are at various stages in the development pipeline. These potential therapies, along with the epidemiology of producers and current treatment options, are the focus of this review.
Topics: Anti-Bacterial Agents; Asia; Gram-Negative Bacteria; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 32690645
DOI: 10.1128/AAC.00397-20 -
International Journal of Molecular... Jul 2020Despite being members of gut microbiota, are associated with many severe infections such as bloodstream infections. The β-lactam drugs have been the cornerstone of... (Review)
Review
Despite being members of gut microbiota, are associated with many severe infections such as bloodstream infections. The β-lactam drugs have been the cornerstone of antibiotic therapy for such infections. However, the overuse of these antibiotics has contributed to select β-lactam-resistant isolates, so that β-lactam resistance is nowadays a major concern worldwide. The production of enzymes that inactivate β-lactams, mainly extended-spectrum β-lactamases and carbapenemases, can confer multidrug resistance patterns that seriously compromise therapeutic options. Further, β-lactam resistance may result in increases in the drug toxicity, mortality, and healthcare costs associated with infections. Here, we summarize the updated evidence about the molecular mechanisms and epidemiology of β-lactamase-mediated β-lactam resistance in , and their potential impact on clinical outcomes of β-lactam-resistant infections.
Topics: Bacterial Proteins; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; beta-Lactam Resistance; beta-Lactamases; beta-Lactams
PubMed: 32708513
DOI: 10.3390/ijms21145090 -
Antimicrobial Agents and Chemotherapy Apr 2022Assigning names to β-lactamase variants has been inconsistent and has led to confusion in the published literature. The common availability of whole genome sequencing...
Assigning names to β-lactamase variants has been inconsistent and has led to confusion in the published literature. The common availability of whole genome sequencing has resulted in an exponential growth in the number of new β-lactamase genes. In November 2021 an international group of β-lactamase experts met virtually to develop a consensus for the way naturally-occurring β-lactamase genes should be named. This document formalizes the process for naming novel β-lactamases, followed by their subsequent publication.
Topics: Consensus; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 35380458
DOI: 10.1128/aac.00333-22 -
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 -
Biomolecules Jul 2021β-Lactams were the first class of antibiotics to be discovered and the second to be introduced into the clinic in the 1940s [...].
β-Lactams were the first class of antibiotics to be discovered and the second to be introduced into the clinic in the 1940s [...].
Topics: Amino Acid Sequence; Structure-Activity Relationship; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 34356610
DOI: 10.3390/biom11070986 -
WIREs Mechanisms of Disease Nov 2022Ceftazidime/avibactam (CAZ/AVI), a combination of ceftazidime and a novel β-lactamase inhibitor (avibactam) that has been approved by the U.S. Food and Drug... (Review)
Review
Ceftazidime/avibactam (CAZ/AVI), a combination of ceftazidime and a novel β-lactamase inhibitor (avibactam) that has been approved by the U.S. Food and Drug Administration, the European Union, and the National Regulatory Administration in China. CAZ/AVI is used mainly to treat complicated urinary tract infections and complicated intra-abdominal infections in adults, as well as to treat patients infected with Carbapenem-resistant Enterobacteriaceae (CRE) susceptible to CAZ/AVI. However, increased clinical application of CAZ/AVI has resulted in the development of resistant strains. Mechanisms of resistance in most of these strains have been attributed to bla mutations, which lead to amino acid substitutions in β-lactamase and changes in gene expression. Resistance to CAZ/AVI is also associated with reduced expression and loss of outer membrane proteins or overexpression of efflux pumps. In this review, the prevalence of CAZ/AVI-resistance bacteria, resistance mechanisms, and selection of detection methods of CAZ/AVI are demonstrated, aiming to provide scientific evidence for the clinical prevention and treatment of CAZ/AVI resistant strains, and provide guidance for the development of new drugs. This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology.
Topics: Adult; Humans; Ceftazidime; Microbial Sensitivity Tests; Anti-Bacterial Agents; beta-Lactamases
PubMed: 35891616
DOI: 10.1002/wsbm.1571 -
Scientific Reports Aug 2019Nonribosomal peptides are assemblages, including antibiotics, of canonical amino acids and other molecules. β-lactam antibiotics act on bacterial cell walls and can be...
Nonribosomal peptides are assemblages, including antibiotics, of canonical amino acids and other molecules. β-lactam antibiotics act on bacterial cell walls and can be cleaved by β-lactamases. β-lactamase activity in humans has been neglected, even though eighteen enzymes have already been annotated such in human genome. Their hydrolysis activities on antibiotics have not been previously investigated. Here, we report that human cells were able to digest penicillin and this activity was inhibited by β-lactamase inhibitor, i.e. sulbactam. Penicillin degradation in human cells was microbiologically demonstrated on Pneumococcus. We expressed a MBLAC2 human β-lactamase, known as an exosome biogenesis enzyme. It cleaved penicillin and was inhibited by sulbactam. Finally, β-lactamases are widely distributed, archaic, and have wide spectrum, including digesting anticancer and β-lactams, that can be then used as nutriments. The evidence of the other MBLAC2 role as a bona fide β-lactamase allows for reassessment of β-lactams and β-lactamases role in humans.
Topics: Anti-Bacterial Agents; Cell Line; Chromatography, High Pressure Liquid; Humans; Hydrolysis; Mass Spectrometry; Microbial Sensitivity Tests; Penicillins; Recombinant Proteins; Streptococcus pneumoniae; Sulbactam; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 31434986
DOI: 10.1038/s41598-019-48723-y -
Current Opinion in Structural Biology Oct 2018Beta-lactamase enzymes mediate the most common forms of gram-negative antibiotic resistance affecting clinical treatment. They also constitute an excellent model system... (Review)
Review
Beta-lactamase enzymes mediate the most common forms of gram-negative antibiotic resistance affecting clinical treatment. They also constitute an excellent model system for the difficult problem of understanding how allosteric mutations can augment catalytic activity of already-competent enzymes. Multiple allosteric mutations have been identified that alter catalytic activity or drug-resistance spectrum in class A beta lactamases, but predicting these in advance continues to be challenging. Here, we review computational techniques based on structure and/or molecular simulation to predict such mutations. Structure-based techniques have been particularly helpful in developing graph algorithms for analyzing critical residues in beta-lactamase function, while classical molecular simulation has recently shown the ability to prospectively predict allosteric mutations increasing beta-lactamase activity and drug resistance. These will ultimately achieve the greatest power when combined with simulation methods that model reactive chemistry to calculate activation free energies directly.
Topics: Allosteric Regulation; Anti-Bacterial Agents; Bacterial Proteins; Catalysis; Drug Resistance, Microbial; Humans; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Mutation; Structure-Activity Relationship; beta-Lactamases
PubMed: 30243041
DOI: 10.1016/j.sbi.2018.09.001