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Natural Polymorphisms in Mycobacterium tuberculosis Conferring Resistance to Delamanid in Drug-Naive Patients.

ABSTRACT: Mutations in the genes of the F420 signaling pathway of Mycobacterium tuberculosis complex, including dnn, fgd1, fbiA, fbiB, fbiC, and fbiD, can lead to delamanid resistance. We searched for such mutations among 129 M. tuberculosis strains from Asia, South America, and Africa using whole-genome sequencing; 70 (54%) strains had at least one mutation in one of the genes. For 10 strains with mutations, we determined the MIC of delamanid. We found one strain from a delamanid-naive patient carrying the natural polymorphism Tyr29del (ddn) that was associated with a critical delamanid MIC.

SUBMITTER: Reichmuth ML

PROVIDER: S-EPMC7577131 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Natural Polymorphisms in Mycobacterium tuberculosis Conferring Resistance to Delamanid in Drug-Naive Patients.

Reichmuth Martina L ML Hömke Rico R Zürcher Kathrin K Sander Peter P Avihingsanon Anchalee A Collantes Jimena J Loiseau Chloé C Borrell Sonia S Reinhard Miriam M Wilkinson Robert J RJ Yotebieng Marcel M Fenner Lukas L Böttger Erik C EC Gagneux Sebastien S Egger Matthias M Keller Peter M PM

Antimicrobial agents and chemotherapy 20201020 11

Mutations in the genes of the F420 signaling pathway of Mycobacterium tuberculosis complex, including dnn, fgd1, fbiA, fbiB, fbiC, and fbiD, can lead to delamanid resistance. We searched for such mutations among 129 M. tuberculosis strains from Asia, South America, and Africa using whole-genome sequencing; 70 (54%) strains had at least one mutation in one of the genes. For 10 strains with mutations, we determined the MIC of delam ...[more]

PMID: 32868333

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Characterization of Genomic Variants Associated with Resistance to Bedaquiline and Delamanid in Naive Mycobacterium tuberculosis Clinical Strains.

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Project description:To understand the response of M. tuberculosis (MTB) to the drug delamanid, we performed transcriptomics on MTB bacilli exposed to the drug.

2018-08-02 | GSE118008 | GEO

Next-Generation Sequencing for Characterizing Drug Resistance-Conferring Mycobacterium tuberculosis Genes from Clinical Isolates in the Ukraine.

Project description:The Ukraine ranks among the top 20 countries with the highest number of multidrug-resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis cases in the world. However, little is known of the genetic diversity, i.e., resistance signatures, in clinical isolates from this region. We analyzed seven of most prevalent MDR/XDR antibiotic resistance-conferring genes from clinical isolates (n = 75) collected from geographically diverse Ukrainian oblasts and the southern Crimean peninsula. Genomic analysis revealed that 6 (8%) were sensitive, 3 (4%) were resistant to at least one antibiotic but were not MDR, 40 (53%) were MDR, and 26 (35%) were XDR. The majority of isolates (81%) were of the Beijing-like lineage. This is the first study to use next-generation sequencing (NGS) of clinical isolates from the Ukraine to characterize mutations in genes conferring M. tuberculosis drug resistance. Several isolates harbored drug resistance signatures that have not been observed in other countries with high-burden tuberculosis. Most notably, the absence of inhA gene promoter mutations, a diversity of mutation types in the rpoB resistance-determining region, and detection of heteroresistance provide a broader understanding of MDR/XDR from this area of the world.

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Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid.

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| S-EPMC8484543 | biostudies-literature

Genome-wide analysis of Mycobacterium tuberculosis polymorphisms reveals lineage-specific associations with drug resistance.

Project description:BackgroundContinuing evolution of the Mycobacterium tuberculosis (Mtb) complex genomes associated with resistance to anti-tuberculosis drugs is threatening tuberculosis disease control efforts. Both multi- and extensively drug resistant Mtb (MDR and XDR, respectively) are increasing in prevalence, but the full set of Mtb genes involved are not known. There is a need for increased sensitivity of genome-wide approaches in order to elucidate the genetic basis of anti-microbial drug resistance and gain a more detailed understanding of Mtb genome evolution in a context of widespread antimicrobial therapy. Population structure within the Mtb complex, due to clonal expansion, lack of lateral gene transfer and low levels of recombination between lineages, may be reducing statistical power to detect drug resistance associated variants.ResultsTo investigate the effect of lineage-specific effects on the identification of drug resistance associations, we applied genome-wide association study (GWAS) and convergence-based (PhyC) methods to multiple drug resistance phenotypes of a global dataset of Mtb lineages 2 and 4, using both lineage-wise and combined approaches. We identify both well-established drug resistance variants and novel associations; uniquely identifying associations for both lineage-specific and -combined GWAS analyses. We report 17 potential novel associations between antimicrobial resistance phenotypes and Mtb genomic variants.ConclusionsFor GWAS, both lineage-specific and -combined analyses are useful, whereas PhyC may perform better in contexts of greater diversity. Unique associations with XDR in lineage-specific analyses provide evidence of diverging evolutionary trajectories between lineages 2 and 4 in response to antimicrobial drug therapy.

| S-EPMC6440112 | biostudies-literature

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