The ability of Mycobacterium 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 the M. tuberculosis glpK gene represents a third type of resistance mechanism. The ability of these glpK 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.
