Beyond Genetic Resistance: Phenotypic Drug Tolerance, Persistence and Diagnostic Blind Spots in Mycobacterium Tuberculosis

Background: Despite major advances in molecular diagnostics, tuberculosis (TB) treatment failure and relapse continue to occur among patients classified as drug-susceptible. Current phenotypic and genotypic drug susceptibility testing (DST) frameworks are designed to detect heritable genetic resistance but fail to capture non-genetic bacterial survival strategies.

Objective: This review critically examines diagnostic blind spots arising from phenotypic drug tolerance and persistence in Mycobacterium tuberculosis and their implications for TB treatment, surveillance, and control.

Main Body: Drug tolerance and persistence are reversible phenotypic states that enable M. tuberculosis to survive bactericidal drug exposure without changes in minimum inhibitory concentrations (MICs). Tolerant population’s exhibit reduced killing kinetics, while persisters represent dormant subpopulations capable of resuming growth after treatment cessation. These survival states evade standard phenotypic and genotypic diagnostics, contributing to genotype–phenotype discordance, prolonged therapy, relapse, and amplification of resistance. Underlying mechanisms include metabolic downregulation, activation of stress-response pathways, toxin–antitoxin systems, and host-induced environmental adaptation. The diagnostic and programmatic consequences of these blind spots are particularly pronounced in high-burden, resource-limited settings.

Conclusion: Beyond genetic resistance, phenotypic drug tolerance and persistence are critical determinants of TB treatment outcomes. Addressing these diagnostic blind spots requires a paradigm shift toward integrating phenotypic survival assessment into diagnostic, therapeutic, and surveillance frameworks to strengthen global TB control.