Complex, dynamic, and diverse phenotypes of stress/antibiotics-induced and natural subpopulations of...

A small proportion of Mycobacterium tuberculosis populations, irrespective of their experimental/host/environmental conditions, successfully survives under stress conditions for long periods by forming natural or stress/antibiotics-induced, phenotypically different but genotypically identical subpopulation(s). This review highlights and describes the complex, dynamic, and diverse spectrum of phenotypic heterogeneity of these subpopulations and the characteristics of their varied response and adaptations to stress/antibiotics for survival. These surviving subpopulations of M. tuberculosis were found in the tuberculosis patients before, during, and after treatment, in the people carrying latent bacilli, in infected animal models, infected macrophages ex vivo, and in in vitro cultures maintained under extremely diverse stress/antibiotics conditions. The phenotypes included slow-growing bacilli, viable but non-culturable bacilli, differentially culturable bacilli, differentially detectable bacilli, directly solid-media culturable and non-culturable bacilli, and bacilli of diverse morphology, size, shape, and stainability. There are naturally evolved subpopulations as well, which also survive and dynamically evolve under stress/antibiotics in vitro, in the host, and environment. The formation of subpopulations with such astounding phenotypic diversity, their stress/antibiotics response, and survival indicate stress/antibiotics-response-specific triggering of diverse biochemical pathways and mechanisms, reflecting the incredibly phenomenal metabolic plasticity of tubercle bacillus. These surviving subpopulations can undergo adaptive evolution under host/antibiotic stress and contribute to poor treatment response and outcome. The molecular and structural study of the features of the diverse phenotypes and the mechanisms of their formation and survival may help to design methods for their detection in patient samples and to formulate strategies for successful and favourable treatment outcome.