-
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 -
Clinical Microbiology Reviews Mar 2020β-Lactam antibiotics have been widely used as therapeutic agents for the past 70 years, resulting in emergence of an abundance of β-lactam-inactivating... (Review)
Review
β-Lactam antibiotics have been widely used as therapeutic agents for the past 70 years, resulting in emergence of an abundance of β-lactam-inactivating β-lactamases. Although penicillinases in challenged the initial uses of penicillin, β-lactamases are most important in Gram-negative bacteria, particularly in enteric and nonfermentative pathogens, where collectively they confer resistance to all β-lactam-containing antibiotics. Critical β-lactamases are those enzymes whose genes are encoded on mobile elements that are transferable among species. Major β-lactamase families include plasmid-mediated extended-spectrum β-lactamases (ESBLs), AmpC cephalosporinases, and carbapenemases now appearing globally, with geographic preferences for specific variants. CTX-M enzymes include the most common ESBLs that are prevalent in all areas of the world. In contrast, KPC serine carbapenemases are present more frequently in the Americas, the Mediterranean countries, and China, whereas NDM metallo-β-lactamases are more prevalent in the Indian subcontinent and Eastern Europe. As selective pressure from β-lactam use continues, multiple β-lactamases per organism are increasingly common, including pathogens carrying three different carbapenemase genes. These organisms may be spread throughout health care facilities as well as in the community, warranting close attention to increased infection control measures and stewardship of the β-lactam-containing drugs in an effort to control selection of even more deleterious pathogens.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bacterial Proteins; Clinical Laboratory Techniques; Drug Resistance, Multiple, Bacterial; Humans; Plasmids; beta-Lactamases; beta-Lactams
PubMed: 32102899
DOI: 10.1128/CMR.00047-19 -
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 -
Antimicrobial Agents and Chemotherapy Aug 2022Modern medicine is threatened by the rising tide of antimicrobial resistance, especially among Gram-negative bacteria, where resistance to β-lactams is most often... (Review)
Review
Modern medicine is threatened by the rising tide of antimicrobial resistance, especially among Gram-negative bacteria, where resistance to β-lactams is most often mediated by β-lactamases. The penicillin and cephalosporin ascendancies were, in their turn, ended by the proliferation of TEM penicillinases and CTX-M extended-spectrum β-lactamases. These class A β-lactamases have long been considered the most important. For carbapenems, however, the threat is increasingly from the insidious rise of a class D carbapenemase, OXA-48, and its close relatives. Over the past 20 years, OXA-48 and "OXA-48-like" enzymes have proliferated to become the most prevalent enterobacterial carbapenemases across much of Europe, Northern Africa, and the Middle East. OXA-48-like enzymes are notoriously difficult to detect because they often cause only low-level resistance to carbapenems, meaning that the true burden is likely underestimated. Despite this, they are associated with carbapenem treatment failures. A highly conserved incompatibility complex IncL plasmid scaffold often carries and may carry other antimicrobial resistance genes, leaving limited treatment options. High conjugation efficiency means that this plasmid is sometimes carried by multiple in a single patient. Producers evade most β-lactam-β-lactamase inhibitor combinations, though promising agents have recently been licensed, notably ceftazidime-avibactam and cefiderocol. The molecular machinery enabling global spread, current treatment options, and the development pipeline of potential new therapies for that produce OXA-48-like β-lactamases form the focus of this review.
Topics: Anti-Bacterial Agents; Carbapenems; Enterobacteriaceae; Humans; Microbial Sensitivity Tests; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 35856662
DOI: 10.1128/aac.00216-22 -
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 -
Epidemiology and Infection Dec 2020The prevalence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae urinary tract infections (UTIs) is increasing worldwide....
The prevalence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae urinary tract infections (UTIs) is increasing worldwide. We investigated the prevalence, clinical findings, impact and risk factors of ESBL E. coli/K. pneumoniae UTI through a retrospective review of the medical records of children with UTI aged <15 years admitted to Prince of Songkla University Hospital, Thailand over 10 years (2004-2013). Thirty-seven boys and 46 girls had ESBL-positive isolates in 102 UTI episodes, compared with 85 boys and 103 girls with non-ESBL isolates in 222 UTI episodes. The age of presentation and gender were not significantly different between the two groups. The prevalence of ESBL rose between 2004 and 2008 before plateauing at around 30-40% per year, with a significant difference between first and recurrent UTI episodes of 27.3% and 46.5%, respectively (P = 0.003). Fever prior to UTI diagnosis was found in 78.4% of episodes in the non-ESBL group and 61.8% of episodes in the ESBL group (P = 0.003). Multivariate analysis indicated that children without fever (odds ratio (OR) 2.14, 95% confidence interval (CI) 1.23-3.74) and those with recurrent UTI (OR 2.67, 95% CI 1.37-5.19) were more likely to yield ESBL on culture. Congenital anomalies of the kidney and urinary tract were not linked to the presence of ESBL UTI. In conclusion, ESBL producers represented one-third of E. coli/K. pneumoniae UTI episodes but neither clinical condition nor imaging studies were predictive of ESBL infections. Recurrent UTI was the sole independent risk factor identified.
Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Female; Humans; Infant; Klebsiella Infections; Klebsiella pneumoniae; Male; Retrospective Studies; Urinary Tract Infections; beta-Lactamases
PubMed: 33327984
DOI: 10.1017/S0950268820003015 -
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