ArticleAntimicrobial agents and chemotherapy2011
Impact of Fgd1 and ddn diversity in Mycobacterium tuberculosis complex on in vitro susceptibility to PA-824.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
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Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it, 65 citations in OpenAlex.
- Systematic review of mutations associated with resistance to the new and repurposed Mycobacterium tuberculosis drugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid.The Journal of antimicrobial chemotherapy · 2020Pooled it
- New and Repurposed Drugs for the Treatment of Active Tuberculosis: An Update for Clinicians.Respiration; international review of thoracic diseases · 2023Review
- Spontaneous Mutational Patterns and Novel Mutations for Delamanid Resistance in Mycobacterium tuberculosis.Antimicrobial agents and chemotherapy · 2022Article
- Review
- Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid.The Journal of antimicrobial chemotherapy · 2022Article
- Delamanid or pretomanid? A Solomonic judgement!The Journal of antimicrobial chemotherapy · 2022Article
- Advances in Key Drug Target Identification and New Drug Development for Tuberculosis.BioMed research international · 2022Review
- Mutations inAntimicrobial agents and chemotherapy · 2020Article
- Molecular mechanisms of underlying genetic factors and associated mutations for drug resistance inEmerging microbes & infections · 2020Review
- Characterization of Genomic Variants Associated with Resistance to Bedaquiline and Delamanid in Naive Mycobacterium tuberculosis Clinical Strains.Journal of clinical microbiology · 2020Article
- Natural Polymorphisms in Mycobacterium tuberculosis Conferring Resistance to Delamanid in Drug-Naive Patients.Antimicrobial agents and chemotherapy · 2020Article
- Whole Genome Sequencing for the Analysis of Drug Resistant Strains ofAntibiotics (Basel, Switzerland) · 2020Review
- Phylogenetically informative mutations in genes implicated in antibiotic resistance in Mycobacterium tuberculosis complex.Genome medicine · 2020Article
- Genetic and Virulence Characteristics of Linezolid and Pretomanid Dual Drug-Resistant Strains Induced fromInfection and drug resistance · 2020Article
- Pretomanid: First Approval.Drugs · 2019Review
- Article
- Whole genome sequencing for drug resistance determination inAfrican journal of laboratory medicine · 2019Article
- Delamanid, Bedaquiline, and Linezolid Minimum Inhibitory Concentration Distributions and Resistance-related Gene Mutations in Multidrug-resistant and Extensively Drug-resistant Tuberculosis in Korea.Annals of laboratory medicine · 2018Article
- Evolution of drug resistance in Mycobacterium tuberculosis: a review on the molecular determinants of resistance and implications for personalized care.The Journal of antimicrobial chemotherapy · 2018Review
- Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis.Frontiers in microbiology · 2018Review
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
PA-824 is a promising drug candidate for the treatment of tuberculosis (TB). It is in phase II clinical trials as part of the first newly designed regimen containing multiple novel antituberculosis drugs (PA-824 in combination with moxifloxacin and pyrazinamide). However, given that the genes involved in resistance against PA-824 are not fully conserved in the Mycobacterium tuberculosis complex (MTBC), this regimen might not be equally effective against different MTBC genotypes. To investigate this question, we sequenced two PA-824 resistance genes (fgd1 [Rv0407] and ddn [Rv3547]) in 65 MTBC strains representing major phylogenetic lineages. The MICs of representative strains were determined using the modified proportion method in the Bactec MGIT 960 system. Our analysis revealed single-nucleotide polymorphisms in both genes that were specific either for several genotypes or for individual strains, yet none of these mutations significantly affected the PA-824 MICs (≤ 0.25 μg/ml). These results were supported by in silico modeling of the mutations identified in Fgd1. In contrast, "Mycobacterium canettii" strains displayed a higher MIC of 8 μg/ml. In conclusion, we found a large genetic diversity in PA-824 resistance genes that did not lead to elevated PA-824 MICs. In contrast, M. canettii strains had MICs that were above the plasma concentrations of PA-824 documented so far in clinical trials. As M. canettii is also intrinsically resistant against pyrazinamide, new regimens containing PA-824 and pyrazinamide might not be effective in treating M. canettii infections. This finding has implications for the design of multiple ongoing clinical trials.
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