The within-host evolution of antimicrobial resistance in Mycobacterium tuberculosis

ABSTRACT

Tuberculosis (TB) has been responsible for the greatest number of human deaths due to an infectious disease in general, and due to antimicrobial resistance (AMR) in particular. The etiological agents of human TB are a closely-related group of human-adapted bacteria that belong to the Mycobacterium tuberculosis complex (MTBC). Understanding how MTBC populations evolve within-host may allow for improved TB treatment and control strategies. In this review, we highlight recent works that have shed light on how AMR evolves in MTBC populations within individual patients. We discuss the role of heteroresistance in AMR evolution, and review the bacterial, patient and environmental factors that likely modulate the magnitude of heteroresistance within-host. We further highlight recent works on the dynamics of MTBC genetic diversity within-host, and discuss how spatial substructures in patients’ lungs, spatiotemporal heterogeneity in antimicrobial concentrations and phenotypic drug tolerance likely modulates the dynamics of MTBC genetic diversity in patients during treatment. We note the general characteristics that are shared between how the MTBC and other bacterial pathogens evolve in humans, and highlight the characteristics unique to the MTBC.

Abstract

Heteroresistance is an important stepping-stone to how an initially monoclonal and drug-susceptible population of Mycobacterium tuberculosis becomes fully resistant to a given antimicrobial during the course of an infection, and this review discusses how bacterial mutation rates, bacterial population size, the number of mutations that can confer antimicrobial resistance (i.e. AMR target size) and the fitness of AMR mutations all modulate the magnitude of heteroresistance.