The defining feature of tuberculosis is the long period of clinical latency during which the causative agent, Mycobacterium tuberculosis (Mtb), grows slowly if at all. It is difficult to overstate the importance of this quiescent behavior, as it likly underlies both the chronic nature of the infection and the relative ineffectiveness of antibiotics. Despite the growing recognition that quiescence is a relatively common microbial response to stress, the physiological state of these slowly- or non-replicating cells has remained enigmatic. To investigate the transition to quiescence, we identified both the genes required for the growth arrest and long-term survival of Mtb during stress-induced stasis, and the metabolic alterations that accompany this transition. Based on these complementary studies, we propose a regulatory cascade that senses host-derived stress, slows bacterial growth, and remodels metabolism for long-term stasis. In this project we will combine high-throughput genetic and biochemical methods to define the structure of this regulatory pathway and determine its ultimate role in promoting bacterial persistence and determining drug efficacy in vivo. We will then characterize the metabolic alterations that are required for the adaptation to quiescence and determine which of these are necessary for survival during stasis. Our goal is to devise new strategies to accelerate tuberculosis therapy through the identification and characterization of cellular pathways that are required for maintaining the quiescent state.
Tuberculosis remains a devastating disease that affects much of the world and is responsible approximately two million deaths every year. Effective treatment of fully drug-susceptible strains of M. tuberculosis requires the administration of multiple antibiotics for at least six months. It has been estimated that reducing treatment duration to two months could both prevent millions of TB cases and slow the emergence of drug resistance. Both the persistence of latent infection and the relatively poor efficacy of antibiotics have been attributed to the presence of slowly- or non-replicating populations of the causative agent, Mycobacterium tuberculosis (Mtb), which are tolerant to both immune insults and antibiotic treatment. We have begun to define the physiology of these drug-tolerant bacterial populations and have demonstrated that disrupting this quiescence program can dramatically improve the efficacy of antibiotics during infection. The proposed project will define the pathways responsible for initiating and maintaining the quiescent state. This information can be used to identifying targets of a new generation of synergistic therapies that could shorten the duration of TB therapy.
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