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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Lacourciere, Karen A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
Schools of Medicine
United States
Zip Code
Prigozhin, Daniil M; Papavinasasundaram, Kadamba G; Baer, Christina E et al. (2016) Structural and Genetic Analyses of the Mycobacterium tuberculosis Protein Kinase B Sensor Domain Identify a Potential Ligand-binding Site. J Biol Chem 291:22961-22969
Lovewell, Rustin R; Sassetti, Christopher M; VanderVen, Brian C (2016) Chewing the fat: lipid metabolism and homeostasis during M. tuberculosis infection. Curr Opin Microbiol 29:30-6
Olive, Andrew J; Sassetti, Christopher M (2016) Metabolic crosstalk between host and pathogen: sensing, adapting and competing. Nat Rev Microbiol 14:221-34
Long, Jarukit E; DeJesus, Michael; Ward, Doyle et al. (2015) Identifying essential genes in Mycobacterium tuberculosis by global phenotypic profiling. Methods Mol Biol 1279:79-95
Murphy, Kenan C; Papavinasasundaram, Kadamba; Sassetti, Christopher M (2015) Mycobacterial recombineering. Methods Mol Biol 1285:177-99
Baer, Christina E; Rubin, Eric J; Sassetti, Christopher M (2015) New insights into TB physiology suggest untapped therapeutic opportunities. Immunol Rev 264:327-43
Feltcher, Meghan E; Gunawardena, Harsha P; Zulauf, Katelyn E et al. (2015) Label-free Quantitative Proteomics Reveals a Role for the Mycobacterium tuberculosis SecA2 Pathway in Exporting Solute Binding Proteins and Mce Transporters to the Cell Wall. Mol Cell Proteomics 14:1501-16
Nambi, Subhalaxmi; Long, Jarukit E; Mishra, Bibhuti B et al. (2015) The Oxidative Stress Network of Mycobacterium tuberculosis Reveals Coordination between Radical Detoxification Systems. Cell Host Microbe 17:829-37
Raimunda, Daniel; Long, Jarukit E; Padilla-Benavides, Teresita et al. (2014) Differential roles for the Co(2+) /Ni(2+) transporting ATPases, CtpD and CtpJ, in Mycobacterium tuberculosis virulence. Mol Microbiol 91:185-97
Shell, Scarlet S; Prestwich, Erin G; Baek, Seung-Hun et al. (2013) DNA methylation impacts gene expression and ensures hypoxic survival of Mycobacterium tuberculosis. PLoS Pathog 9:e1003419

Showing the most recent 10 out of 24 publications