ArticlePLoS pathogens2021
Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline.
Article in PLoS pathogens, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 42 citations in OpenAlex.
- CRISPRi-mediatedAntimicrobial agents and chemotherapy · 2026Article
- NTM-host matched infection models for the classification of drug efficacy against rapid and slow growing nontuberculous mycobacteria species.Scientific reports · 2026Article
- Selectivity of the Time-DependentACS chemical biology · 2025Article
- CRISPRi-mediated validation of candidatebioRxiv : the preprint server for biology · 2025Article
- Mycobacteria susceptibility to epetraborole: how far can it go?The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease · 2025Article
- Genome-wide Screening of the Escherichia coli Keio Knockout Collection Identifies Genetic Determinants of Epetraborole Hypersusceptibility.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2025Article
- Repurposing drugs to advance the treatment of Buruli ulcer.Antimicrobial agents and chemotherapy · 2025Article
- Time-Dependent Inhibition of Leucyl-tRNA-Synthetase (LeuRS): Insight into Target Vulnerability.ACS infectious diseases · 2025Article
- In vitro susceptibility of 147 international clinical Mycobacterium abscessus isolates to epetraborole and comparators by broth microdilution.The Journal of antimicrobial chemotherapy · 2025Article
- Activity of combinations of bactericidal and bacteriostatic compounds inFrontiers in microbiology · 2025Review
- Toward better cures forClinical microbiology reviews · 2024Review
- Oral oxaborole MRX-5 exhibits efficacy against pulmonaryAntimicrobial agents and chemotherapy · 2024Article
- An open-access dashboard to interrogate the genetic diversity of Mycobacterium tuberculosis clinical isolates.Scientific reports · 2024Article
- Screening of the Pandemic Response Box library identified promising compound candidate drug combinations against extensively drug-resistant Acinetobacter baumannii.Scientific reports · 2024Article
- Efficacy of epetraborole againstAntimicrobial agents and chemotherapy · 2024Article
- Preclinical murine models for the testing of antimicrobials against Mycobacterium abscessus pulmonary infections: Current practices and recommendations.Tuberculosis (Edinburgh, Scotland) · 2024Review
- Diving into drug-screening: zebrafish embryos as an in vivo platform for antimicrobial drug discovery and assessment.FEMS microbiology reviews · 2024Review
- In Vitro Evaluation of Drug-Drug Interaction Potential of Epetraborole, a Novel Bacterial Leucyl-tRNA Synthetase Inhibitor.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Screening of MMV pandemic response and pathogen box compounds against pan-drug-resistantNew microbes and new infections · 2023Article
- Repurposing miconazole and tamoxifen for the treatment of Mycobacterium abscessus complex infections through in silico chemogenomics approach.World journal of microbiology & biotechnology · 2023Article
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mycobacterium abscessus is the most common rapidly growing non-tuberculous mycobacteria to cause pulmonary disease in patients with impaired lung function such as cystic fibrosis. M. abscessus displays high intrinsic resistance to common antibiotics and inducible resistance to macrolides like clarithromycin. As such, M. abscessus is clinically resistant to the entire regimen of front-line M. tuberculosis drugs, and treatment with antibiotics that do inhibit M. abscessus in the lab results in cure rates of 50% or less. Here, we identified epetraborole (EPT) from the MMV pandemic response box as an inhibitor against the essential protein leucyl-tRNA synthetase (LeuRS) in M. abscessus. EPT protected zebrafish from lethal M. abscessus infection and did not induce self-resistance nor against clarithromycin. Contrary to most antimycobacterials, the whole-cell activity of EPT was greater against M. abscessus than M. tuberculosis, but crystallographic and equilibrium binding data showed that EPT binds LeuRSMabs and LeuRSMtb with similar residues and dissociation constants. Since EPT-resistant M. abscessus mutants lost LeuRS editing activity, these mutants became susceptible to misaminoacylation with leucine mimics like the non-proteinogenic amino acid norvaline. Proteomic analysis revealed that when M. abscessus LeuRS mutants were fed norvaline, leucine residues in proteins were replaced by norvaline, inducing the unfolded protein response with temporal changes in expression of GroEL chaperonins and Clp proteases. This supports our in vitro data that supplementation of media with norvaline reduced the emergence of EPT mutants in both M. abscessus and M. tuberculosis. Furthermore, the combination of EPT and norvaline had improved in vivo efficacy compared to EPT in a murine model of M. abscessus infection. Our results emphasize the effectiveness of EPT against the clinically relevant cystic fibrosis pathogen M. abscessus, and these findings also suggest norvaline adjunct therapy with EPT could be beneficial for M. abscessus and other mycobacterial infections like tuberculosis.
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