ArticleEBioMedicine2016
Paradoxical Hypersusceptibility of Drug-resistant Mycobacteriumtuberculosis to β-lactam Antibiotics.
Article in EBioMedicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed.
- Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis: The COMRADE Randomized, Phase 2A Clinical Trial.American journal of respiratory and critical care medicine · 2022Trial
- Genetic interference of distinctive Mycobacterium tuberculosis peptidoglycan modifications enhances β-lactam susceptibility and reveals expression-sensitive host immune dynamics.Scientific reports · 2026Article
- Effects of CwlM, a peptidoglycan synthesis regulator, on beta-lactam tolerance and host-pathogen interactions.BMC microbiology · 2025Article
- Peptidoglycan LD-Transpeptidases.Antibiotics (Basel, Switzerland) · 2025Review
- Sanfetrinem, an oral β-lactam antibiotic repurposed for the treatment of tuberculosis.Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy · 2025Article
- Sanfetrinem, an oral β-lactam antibiotic repurposed for the treatment of tuberculosis.bioRxiv : the preprint server for biology · 2024Article
- Ethambutol and meropenem/clavulanate synergy promotes enhanced extracellular and intracellular killing ofAntimicrobial agents and chemotherapy · 2024Article
- Positive epistasis drives clavulanic acid resistance in double mutant libraries of BlaC β-lactamase.Communications biology · 2024Article
- Structural Insights into the Penicillin-Binding Protein 4 (DacB) fromInternational journal of molecular sciences · 2024Article
- Clinical utilization of multiple antibodies ofAnnals of medicine · 2023Observational
- Genome-Wide Association Studies (GWAS) Approaches for the Detection of Genetic Variants Associated with Antibiotic Resistance: A Systematic Review.Microorganisms · 2023Review
- Article
- Mycobacterium tuberculosis β-lactamase variant reduces sensitivity to ampicillin/avibactam in a zebrafish-Mycobacterium marinum model of tuberculosis.Scientific reports · 2023Article
- The evolution of antibiotic resistance is associated with collateral drug phenotypes in Mycobacterium tuberculosis.Nature communications · 2023Article
- CRISPRi-mediated characterization of novel anti-tuberculosis targets: Mycobacterial peptidoglycan modifications promote beta-lactam resistance and intracellular survival.Frontiers in cellular and infection microbiology · 2023Article
- Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
- Uncovering Beta-Lactam Susceptibility Patterns in Clinical Isolates of Mycobacterium tuberculosis through Whole-Genome Sequencing.Microbiology spectrum · 2022Article
- Susceptibility of β-Lactam Antibiotics and Genetic Mutation of Drug-Resistant Mycobacterium tuberculosis Isolates in Korea.Tuberculosis and respiratory diseases · 2022Article
- Identification of drivers of mycobacterial resistance to peptidoglycan synthesis inhibitors.Frontiers in microbiology · 2022Article
- The Epistatic Landscape of Antibiotic Resistance of Different Clades ofAntibiotics (Basel, Switzerland) · 2021Article
Corrections and comments
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Authors and funding
12 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mycobacterium tuberculosis (M. tuberculosis) is considered innately resistant to β-lactam antibiotics. However, there is evidence that susceptibility to β-lactam antibiotics in combination with β-lactamase inhibitors is variable among clinical isolates, and these may present therapeutic options for drug-resistant cases. Here we report our investigation of susceptibility to β-lactam/β-lactamase inhibitor combinations among clinical isolates of M. tuberculosis, and the use of comparative genomics to understand the observed heterogeneity in susceptibility. Eighty-nine South African clinical isolates of varying first and second-line drug susceptibility patterns and two reference strains of M. tuberculosis underwent minimum inhibitory concentration (MIC) determination to two β-lactams: amoxicillin and meropenem, both alone and in combination with clavulanate, a β-lactamase inhibitor. 41/91 (45%) of tested isolates were found to be hypersusceptible to amoxicillin/clavulanate relative to reference strains, including 14/24 (58%) of multiple drug-resistant (MDR) and 22/38 (58%) of extensively drug-resistant (XDR) isolates. Genome-wide polymorphisms identified using whole-genome sequencing were used in a phylogenetically-aware linear mixed model to identify polymorphisms associated with amoxicillin/clavulanate susceptibility. Susceptibility to amoxicillin/clavulanate was over-represented among isolates within a specific clade (LAM4), in particular among XDR strains. Twelve sets of polymorphisms were identified as putative markers of amoxicillin/clavulanate susceptibility, five of which were confined solely to LAM4. Within the LAM4 clade, 'paradoxical hypersusceptibility' to amoxicillin/clavulanate has evolved in parallel to first and second-line drug resistance. Given the high prevalence of LAM4 among XDR TB in South Africa, our data support an expanded role for β-lactam/β-lactamase inhibitor combinations for treatment of drug-resistant M. tuberculosis.
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