β-Lactams and β-Lactamase Inhibitors: An Overview

Bush, Karen; Bradford, Patricia A.

doi:10.1101/cshperspect.a025247

Cited by 785 publications

(690 citation statements)

References 144 publications

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“…The penicillin-binding protein transpeptidases were among the first validated antibiotic targets, offering the main biochemical target of the β-lactam antibiotics. 99 Sortases graft secreted proteins to the bacterial cell wall in Gram-positive bacteria, many of which are essential for infection and thus are potential targets for antivirulence compounds. 100 For example, synthetic 3,6-disubstituted triazolothiadiazole inhibitors of S. aureus sortase have shown efficacy in a mouse model of infection.…”

Section: Other Protease Antibacterial Targetsmentioning

confidence: 99%

Bacterial proteases, untapped antimicrobial drug targets

2016

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Bacterial proteases are an extensive collection of enzymes that have vital roles in cell viability, stress response and pathogenicity. Although their perturbation clearly offers the potential for antimicrobial drug development, both as traditional antibiotics and anti-virulence drugs, they are not yet the target of any clinically used therapeutics. Here we describe the potential for and recent progress in the development of compounds targeting bacterial proteases with a focus on AAA+ family proteolytic complexes and signal peptidases (SPs). Caseinolytic protease (ClpP) belongs to the AAA+ family of proteases, a group of multimeric barrel-shaped complexes whose activity is tightly regulated by associated AAA+ ATPases. The opportunity for chemical perturbation of these complexes is demonstrated by compounds targeting ClpP for inhibition, activation or perturbation of its associated ATPase. Meanwhile, SPs are also a proven antibiotic target. Responsible for the cleavage of targeting peptides during protein secretion, both type I and type II SPs have been successfully targeted by chemical inhibitors. As the threat of pan-antibiotic resistance continues to grow, these and other bacterial proteases offer an arsenal of novel antibiotic targets ripe for development.

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Section: Other Protease Antibacterial Targetsmentioning

confidence: 99%

Bacterial proteases, untapped antimicrobial drug targets

2016

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“…The irst β-lactam antibiotic was 'penicillin G' in the beginning of 1940s [1]. Afterwards, naturally occurring penicillin was 'penicillin V' which was an oral formulation, still in use for the therapeutic purposes.…”

Section: Classes Of Beta (β)-Lactam Antibioticsmentioning

confidence: 99%

“…Development of new β-lactam group of antibiotics generally depends on enhancing the spectrum eiciency against the pathogenic bacteria. Besides, resistance mechanisms with special features may be targeted [1].…”

Section: Classes Of Beta (β)-Lactam Antibioticsmentioning

confidence: 99%

“…β-lactam or β-lactamase inhibitor antibiotics are substances that disrupt bacterial cell-wall formation via penicillin-binding proteins (PBPs) where they bind covalently at the terminal step of peptidoglycan cross-linking in bacteria [1]. The irst generation of β-lactam antibiotics were penicillins, followed by cephalosporins; later carbapenems and monocyclic β-lactams that have been recently introduced and are currently in service for the treatment of infectious disease caused by pathogenic bacteria [2].…”

Section: Introductionmentioning

confidence: 99%

“…However, the therapy with β-lactam antibiotics remains unresolved since β-lactamase resistance is disseminating rapidly among pathogenic bacteria. The most serious types of β-lactamase resistance today are extended-spectrum β-lactamases (ESBLs), carbapenemases and metallo-β-lactamases (MBLs) [1,4,5].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Toxicity of β-Lactam Antibiotics: Pathophysiology, Molecular Biology and Possible Recovery Strategies

Bozcal¹,

Dagdeviren²

2017

Poisoning - From Specific Toxic Agents to Novel Rapid and Simplified Techniques for Analysis

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Beta (β)-lactam antibiotics are wide-spectrum antibiotics used for various bacterial infections. The aim of this chapter is to summarize the knowledge about the toxicity of β-lactam antibiotics and issues associated to their inappropriate use. This review has highlighted that β-lactam antibiotics are a group of products that have a chemical structure characterized by a β-lactam ring and are one of the most common antibacterial agents. However, due to the inappropriate use including abuse and misuse, resistance to the β-lactam antibiotics is currently a global crisis. Moreover, even when used appropriately, they have been linked to triggering allergic reactions like urticaria, bronchoconstriction, also severe conditions like immune-mediated haemolytic anaemia and intravascular haemolysis. It is known that some β-lactam antibiotics are neurotoxic, some are nephrotoxic, some are genotoxic and some are toxic to urogenital system. Several factors are involved in the occurrence of toxic efects including the dosage and renal status. Several strategies are possible to overcome β-lactam antibiotics-triggered toxicity, including rational prescribing, substitution combination and phage therapy which seems promising. Public health education for clinical teams and patients is essential in ensuring that this group of antibiotics are retained in therapeutics.

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Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis

Monti

Bradić

Marzaroli

et al. 2023

JAMA

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ImportanceMeropenem is a widely prescribed β-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes.ObjectiveTo determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis.Design, Setting, and ParticipantsA double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022.InterventionsPatients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304).Main Outcomes and MeasuresThe primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events.ResultsAll 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96 [95% CI, 0.81-1.13], P = .60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients).Conclusions and RelevanceIn critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28.Trial RegistrationClinicalTrials.gov Identifier: NCT03452839

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β-Lactams and β-Lactamase Inhibitors: An Overview

Cited by 785 publications

References 144 publications

Bacterial proteases, untapped antimicrobial drug targets

Bacterial proteases, untapped antimicrobial drug targets

Toxicity of β-Lactam Antibiotics: Pathophysiology, Molecular Biology and Possible Recovery Strategies

Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis

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