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Significance The ability ofMycobacterium tuberculosis to survive during prolonged treatment has been attributed to either transient stress responses or fixed heritable drug-resistance–producing mutations. We show that phase-variation in theM. tuberculosis glpK gene represents a third type of resistance mechanism. The ability of theseglpK mutants to grow slowly and then rapidly revert suggests that these transiently heritable changes may also explain how a hidden population of drug-tolerant bacteria develops during tuberculosis treatment. As a genetically trackable cause of drug tolerance,M. tuberculosis glpK mutants provides a unique opportunity to study these phenomena at a cellular and mechanistic level. These mutants could also be used for developing drugs that target tolerant populations, leading to more rapid and effective tuberculosis treatments.

Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance