Abstract
Genomic studies of Mycobacterium tuberculosis bacteria have revealed loci associated with resistance to anti-tuberculosis drugs. However, the molecular consequences of polymorphism within these candidate loci remain poorly understood. To address this, we have used computational tools to quantify the effects of point mutations conferring resistance to three major anti-tuberculosis drugs, isoniazid (n = 189), rifampicin (n = 201) and D-cycloserine (n = 48), within their primary targets, katG, rpoB, and alr. Notably, mild biophysical effects brought about by high incidence mutations were considered more tolerable, while different structural effects brought about by haplotype combinations reflected differences in their functional importance. Additionally, highly destabilising mutations such as alr Y388, highlighted a functional importance of the wildtype residue. Our qualitative analysis enabled us to relate resistance mutations onto a theoretical landscape linking enthalpic changes with phenotype. Such insights will aid the development of new resistance-resistant drugs and, via an integration into predictive tools, in pathogen surveillance.
Highlights
Tuberculosis disease (TB), caused by bacteria in the Mycobacterium tuberculosis complex, continues to have a profound impact on global health
These mutations may manifest resistance via different mechanisms, affecting drug activation in the case of prodrugs, its entry to the target via drug permeability, or the drug target itself[7,15]. These genetically acquired mechanisms are influenced by factors such as: the genetic differences between lineages and especially differences in mutation rates[16]; epistatic interactions between mutations within the genetic background of M. tuberculosis[17]; and the dynamics within a clonal population that lead to competition within a host between sub-populations possessing emergent resistance associated mutations[14,18]
Genetic variants, including nsSNPs, present within drug targets and drug-activating enzymes have been identified as a main cause of drug resistance in TB7
Summary
Tuberculosis disease (TB), caused by bacteria in the Mycobacterium tuberculosis complex, continues to have a profound impact on global health. A major route to resistance is acquired resistance principally via genetic polymorphism or mutations, including single nucleotide polymorphisms (SNPs), insertions and deletions (indels) and occasionally large deletions in genes coding for drug-targets or -converting enzymes in the M. tuberculosis genome (size 4.4 Mbp)[7]. These mutations may manifest resistance via different mechanisms, affecting drug activation in the case of prodrugs, its entry to the target via drug permeability, or the drug target itself[7,15]. These genetically acquired mechanisms are influenced by factors such as: the genetic differences between lineages and especially differences in mutation rates[16]; epistatic interactions between mutations within the genetic background of M. tuberculosis[17]; and the dynamics within a clonal population that lead to competition within a host between sub-populations possessing emergent resistance associated mutations[14,18]
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