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Phylogenetically informative mutations in genes implicated in antibiotic resistance in Mycobacterium tuberculosis complex.
- Source :
- Genome Medicine; 3/6/2020, Vol. 12 Issue 1, p1-8, 8p
- Publication Year :
- 2020
-
Abstract
- Background: A comprehensive understanding of the pre-existing genetic variation in genes associated with antibiotic resistance in the Mycobacterium tuberculosis complex (MTBC) is needed to accurately interpret whole-genome sequencing data for genotypic drug susceptibility testing (DST). Methods: We investigated mutations in 92 genes implicated in resistance to 21 anti-tuberculosis drugs using the genomes of 405 phylogenetically diverse MTBC strains. The role of phylogenetically informative mutations was assessed by routine phenotypic DST data for the first-line drugs isoniazid, rifampicin, ethambutol, and pyrazinamide from a separate collection of over 7000 clinical strains. Selected mutations/strains were further investigated by minimum inhibitory concentration (MIC) testing. Results: Out of 547 phylogenetically informative mutations identified, 138 were classified as not correlating with resistance to first-line drugs. MIC testing did not reveal a discernible impact of a Rv1979c deletion shared by M. africanum lineage 5 strains on resistance to clofazimine. Finally, we found molecular evidence that some MTBC subgroups may be hyper-susceptible to bedaquiline and clofazimine by different loss-of-function mutations affecting a drug efflux pump subunit (MmpL5). Conclusions: Our findings underline that the genetic diversity in MTBC has to be studied more systematically to inform the design of clinical trials and to define sound epidemiologic cut-off values (ECOFFs) for new and repurposed anti-tuberculosis drugs. In that regard, our comprehensive variant catalogue provides a solid basis for the interpretation of mutations in genotypic as well as in phenotypic DST assays. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 1756994X
- Volume :
- 12
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Genome Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 142104841
- Full Text :
- https://doi.org/10.1186/s13073-020-00726-5