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. 2020 Mar 6;12(1):27.
doi: 10.1186/s13073-020-00726-5.

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

Matthias Merker  1   2 , Thomas A Kohl  3   4 , Ivan Barilar  3   4 , Sönke Andres  5 , Philip W Fowler  6 , Erja Chryssanthou  7   8 , Kristian Ängeby  9 , Pontus Jureen  10 , Danesh Moradigaravand  11 , Julian Parkhill  12 , Sharon J Peacock  13 , Thomas Schön  14   15 , Florian P Maurer  5   16 , Timothy Walker  6 , Claudio Köser  17 , Stefan Niemann  3   4
Affiliations

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

Matthias Merker et al. Genome Med. .

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.

Keywords: Benign mutations; Drug resistance; Intrinsic resistance; Mycobacterium tuberculosis.

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Conflict of interest statement

CUK is a consultant for the WHO Regional Office for Europe, Becton Dickinson, and QuantuMDx Group Ltd. CUK is an unpaid advisor to GenoScreen and consulted for the Foundation for Innovative New Diagnostics, which involved work for Cepheid Inc., Hain Lifescience, and WHO. The Bill & Melinda Gates Foundation and Hain Lifescience covered CUK’s travel and accommodation to present at meetings. The Global Alliance for TB Drug Development Inc. and Otsuka Novel Products GmbH have supplied CUK with antibiotics for in vitro research. YD Diagnostics has provided CUK with assays for an evaluation. JP is a paid consultant to Next Gen Diagnostics. All remaining authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
MTBC phylogeny. ML phylogeny based on 42,760 SNPs from 405 genomes using a general time-reversible substitution model and 1000 resamples. Seven major MTBC lineages and animal-adapted species are highlighted. Where warranted, these were differentiated further into subgroups (as shown on the circumference of the figure). Red dots indicate branches (n = 334) with a resampling support of > 0.9 and which were investigated for branch-specific mutations in 92 genes implicated in antibiotic resistance
See this image and copyright information in PMC

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