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<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>A comprehensive understanding of the pre-existing genetic variation in genes associated with antibiotic resistance in the <jats:italic>Mycobacterium tuberculosis</jats:italic> complex (MTBC) is needed to accurately interpret whole-genome sequencing data for genotypic drug susceptibility testing (DST).</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>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 <jats:italic>Rv1979c</jats:italic> deletion shared by <jats:italic>M. africanum</jats:italic> 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).</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec>

Original publication

DOI

10.1186/s13073-020-00726-5

Type

Journal

Genome Medicine

Publisher

Springer Science and Business Media LLC

Publication Date

12/2020

Volume

12