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.
journal_name
Genome Medjournal_title
Genome medicineauthors
Merker M,Kohl TA,Barilar I,Andres S,Fowler PW,Chryssanthou E,Ängeby K,Jureen P,Moradigaravand D,Parkhill J,Peacock SJ,Schön T,Maurer FP,Walker T,Köser C,Niemann Sdoi
10.1186/s13073-020-00726-5subject
Has Abstractpub_date
2020-03-06 00:00:00pages
27issue
1issn
1756-994Xpii
10.1186/s13073-020-00726-5journal_volume
12pub_type
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