Abstract
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).
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 minimum inhibitory concentration testing and routine phenotypic DST data from a separate collection of over 7,000 strains.
Out of 547 phylogenetically informative mutations identified, 138 were classified as not correlating with resistance. We found new evidence of intrinsic resistance to clofazimine and hypothesise that some MTBC subgroups may be hyper-susceptible to bedaquiline and clofazimine.
Our findings underline that the genetic diversity in MTBC has to be studied more systematically to inform the design of clinical trials and genotypic as well as phenotypic DST assays.
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 minimum inhibitory concentration testing and routine phenotypic DST data from a separate collection of over 7,000 strains.
Out of 547 phylogenetically informative mutations identified, 138 were classified as not correlating with resistance. We found new evidence of intrinsic resistance to clofazimine and hypothesise that some MTBC subgroups may be hyper-susceptible to bedaquiline and clofazimine.
Our findings underline that the genetic diversity in MTBC has to be studied more systematically to inform the design of clinical trials and genotypic as well as phenotypic DST assays.
| Original language | English |
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| Publication status | Published - 2019 |
