Our goal is to try to understand the roles of functionally-uncharacterized genes in M. tuberculosis. We will focus on genes that are important for the growth and survival of the bacterium under conditions likely to be relevant to infection, and use multiple approaches to define phenotypes and key interactions to reveal function. We will select targets using existing genome wide screening information. Each target will be investigated using parallel independent approaches to increase the chances of success. Our overall goal is to define function using the GO (gene ontology) definitions of molecular function, cellular process and/or biological process. We will attempt to determine as many of these as possible for each target. This will be accomplished through the following objectives: Objective 1. Identify phenotypes for underexpressing strains (with Core E) Objective 2. Identify interacting genes and proteins (with Cores, C, D and E) Objective 3. Identify substrates/products of potential enzymes (with Cores B and E) Objective 4. Confirm putative interacting genes and pathways (with Cores B-E).

Public Health Relevance

Tuberculosis is an important global health problem, killing millions each year. Our rudimentary under-standing of the basic physiology underlying M. tuberculosis infection hampers our efforts to develop new drugs and vaccines. By functionally-characterizing the genes used by M. tuberculosis to cause disease, we will develop a deeper understanding of the pathogenic process and define more effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI107774-02
Application #
8738886
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Lehmann, Johannes; Cheng, Tan-Yun; Aggarwal, Anup et al. (2018) An Antibacterial ?-Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis. Angew Chem Int Ed Engl 57:348-353
Gerrick, Elias R; Barbier, Thibault; Chase, Michael R et al. (2018) Small RNA profiling in Mycobacterium tuberculosis identifies MrsI as necessary for an anticipatory iron sparing response. Proc Natl Acad Sci U S A 115:6464-6469
Sakatos, Alexandra; Babunovic, Gregory H; Chase, Michael R et al. (2018) Posttranslational modification of a histone-like protein regulates phenotypic resistance to isoniazid in mycobacteria. Sci Adv 4:eaao1478
Xu, Weizhen; DeJesus, Michael A; Rücker, Nadine et al. (2017) Chemical Genetic Interaction Profiling Reveals Determinants of Intrinsic Antibiotic Resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 61:
Guinn, Kristine M; Rubin, Eric J (2017) Tuberculosis: Just the FAQs. MBio 8:
Rego, E Hesper; Audette, Rebecca E; Rubin, Eric J (2017) Deletion of a mycobacterial divisome factor collapses single-cell phenotypic heterogeneity. Nature 546:153-157
Jansen, Robert S; Rhee, Kyu Y (2017) Emerging Approaches to Tuberculosis Drug Development: At Home in the Metabolome. Trends Pharmacol Sci 38:393-405
Köster, Stefan; Upadhyay, Sandeep; Chandra, Pallavi et al. (2017) Mycobacterium tuberculosis is protected from NADPH oxidase and LC3-associated phagocytosis by the LCP protein CpsA. Proc Natl Acad Sci U S A 114:E8711-E8720
Rock, Jeremy M; Hopkins, Forrest F; Chavez, Alejandro et al. (2017) Programmable transcriptional repression in mycobacteria using an orthogonal CRISPR interference platform. Nat Microbiol 2:16274
Mishra, Bibhuti B; Lovewell, Rustin R; Olive, Andrew J et al. (2017) Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis. Nat Microbiol 2:17072

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