Mutation rate and the emergence of drug resistance in Mycobacterium tuberculosis.
The emergence and spread of multidrug-resistant strains of Mycobacterium tuberculosis remains a major concern of tuberculosis control programmes worldwide, as treatment depends on low-efficacy, toxic compounds that often lead to poor outcomes. M. tuberculosis develops drug resistance exclusively through chromosomal mutations, in particular single-nucleotide polymorphisms. Moreover, in laboratory assays the organism exhibits a spontaneous mutation rate that is at the lower end of the bacterial spectrum. Despite this, whole-genome sequencing technology has identified unexpected genetic diversity among clinical M. tuberculosis populations. This suggests that the mycobacterial mutation rate may be modulated within the host and, in turn, implies a potential role for constitutive and/or transient mutator strains in adaptive evolution. It also raises the possibility that environmental factors might act as key mutagens during M. tuberculosis infection. Here we consider the elements that might influence the mycobacterial mutation rate in vivo and evaluate the potential roles of constitutive and transient mutator states in the generation of drug resistance mutations. In addition, we identify key research questions that will influence future efforts to develop novel therapeutic strategies for a disease that continues to impose a significant global health burden.
DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, US/MRC Centre for Molecular and Cellular Biology , Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063, Tygerberg 7505, South Africa.
M
M
McGrath
N C
NC
Gey van Pittius
P D
PD
van Helden
R M
RM
Warren
D F
DF
Warner
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D006801:Humans; D059645:Mutation Rate; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics*; D014376:Tuberculosis / Q000188:drug therapy / Q000235:genetics* / Q000382:microbiology*
D000995:Antitubercular Agents
adaptive mutagenesis; constitutive mutator; evolution; genetic diversity; transient mutator