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Phylogenetically informative mutations in genes implicated in antibiotic resistance in Mycobacterium tuberculosis complex

Authors
  • Merker, Matthias1, 2
  • Kohl, Thomas A.1, 2
  • Barilar, Ivan1, 2
  • Andres, Sönke3
  • Fowler, Philip W.4
  • Chryssanthou, Erja5, 6
  • Ängeby, Kristian6
  • Jureen, Pontus7
  • Moradigaravand, Danesh8
  • Parkhill, Julian9
  • Peacock, Sharon J.9
  • Schön, Thomas10, 11
  • Maurer, Florian P.3, 12
  • Walker, Timothy4
  • Köser, Claudio9
  • Niemann, Stefan1, 2
  • 1 German Center for Infection Research (DZIF), Partner site Hamburg-Lübeck-Borstel-Riems, Borstel, Germany , Borstel (Germany)
  • 2 Research Center Borstel, Parkallee 1, Borstel, 23845, Germany , Borstel (Germany)
  • 3 Research Center Borstel, Borstel, Germany , Borstel (Germany)
  • 4 University of Oxford, Oxford, UK , Oxford (United Kingdom)
  • 5 Karolinska University Hospital, Solna, Stockholm, Sweden , Stockholm (Sweden)
  • 6 Karolinska Institute, Stockholm, Sweden , Stockholm (Sweden)
  • 7 Public Health Agency of Sweden, Solna, Sweden , Solna (Sweden)
  • 8 University of Birmingham, Birmingham, UK , Birmingham (United Kingdom)
  • 9 University of Cambridge, Cambridge, UK , Cambridge (United Kingdom)
  • 10 Kalmar County Hospital, Kalmar, Sweden , Kalmar (Sweden)
  • 11 Linköping University, Linköping, Sweden , Linköping (Sweden)
  • 12 University Medical Center Hamburg-Eppendorf, Hamburg, Germany , Hamburg (Germany)
Type
Published Article
Journal
Genome Medicine
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Mar 06, 2020
Volume
12
Issue
1
Identifiers
DOI: 10.1186/s13073-020-00726-5
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundA 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).MethodsWe 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.ResultsOut 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).ConclusionsOur 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.

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