The Epistatic Landscape of Antibiotic Resistance of Different Clades of Mycobacterium tuberculosis.

Dillon Muzondiwa,Oleg N Reva,Hleliwe Hlanze

doi:10.3390/antibiotics10070857

Dillon Muzondiwa, Oleg N Reva + Show 1 more

Open Access

https://doi.org/10.3390/antibiotics10070857

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Journal: Antibiotics	Publication Date: Jul 15, 2021
Citations: 8	License type: CC BY 4.0

Affiliation: University of Pretoria

Abstract

Drug resistance (DR) remains a global challenge in tuberculosis (TB) control. In order to develop molecular-based diagnostic methods to replace the traditional culture-based diagnostics, there is a need for a thorough understanding of the processes that govern TB drug resistance. The use of whole-genome sequencing coupled with statistical and computational methods has shown great potential in unraveling the complexity of the evolution of DR-TB. In this study, we took an innovative approach that sought to determine nonrandom associations between polymorphic sites in Mycobacterium tuberculosis (Mtb) genomes. Attributable risk statistics were applied to identify the epistatic determinants of DR in different clades of Mtb and the possible evolutionary pathways of DR development. It was found that different lineages of Mtb exploited different evolutionary trajectories towards multidrug resistance and compensatory evolution to reduce the DR-associated fitness cost. Epistasis of DR acquisition is a new area of research that will aid in the better understanding of evolutionary biological processes and allow predicting upcoming multidrug-resistant pathogens before a new outbreak strikes humanity.

Highlights

Despite being a disease of antiquity, TB caused by Mycobacterium tuberculosis (Mtb) remains one of the leading killers globally, with approximately 10 million new cases annually and about 2 billion people infected globally [1]
This study includes an analysis of 2501 Mtb isolates available from the GMTV database, which underwent culture-based drug susceptibility testing and lineage classification [36]
Pairs of polymorphic sites within selected Mtb genomes showing a nonrandom distribution were analyzed using Levin’s attributable risk statistic [37], which predicts the likelihood of a subordinate substitution of the allelic state B to the state b if a primary mutation at another locus from the allelic state A to the state a already took place

Summary

Introduction

Despite being a disease of antiquity, TB caused by Mycobacterium tuberculosis (Mtb) remains one of the leading killers globally, with approximately 10 million new cases annually and about 2 billion people infected globally [1]. While a global decrease in TB incidence is reported, drug-resistant TB (DR-TB) has been identified as a cause for concern in global efforts to eradicate TB [2]. According to a report by the World Health Organization (WHO) in 2017, approximately 4.1% of new TB cases and 19% of previously treated cases were classified as multidrug-resistant TB (MDR-TB). Apart from chromosomal mutations, the intrinsic resistance due to the bacterium’s lipid-rich cell wall and efflux pumps has limited the number of drugs that can treat TB [5,9]. Unlike in most bacterial pathogens, horizontal gene transfer does not play a role in the acquisition of DR in Mtb. Unlike in most bacterial pathogens, horizontal gene transfer does not play a role in the acquisition of DR in Mtb For this reason, research has mostly focused on identifying multivariate associations between SNPs in the Mtb genome and the resistant phenotype. The application of mathematical methods in tandem with WGS and other related TB data has proved to be vital in exploring the associations between TB variants [5,14,15,16]

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