Tuberculosis remains the leading infectious cause of death worldwide, accounting for 2-3 million human deaths each year. Multi-drug resistant strains of M. tuberculosis have emerged that are significantly more difficult and expensive to treat. This program has focused on the development of genetic tools to analyze the molecular basis of drug resistance and virulence of M. tuberculosis. Relevant to both goals is the phenomenon of M. tuberculosis latency. Within the infected host, a subpopulation of tubercle bacilli enters a non-replicating latent state that confers phenotypic resistance to both antibiotics and host immune mechanisms. These latent """"""""persisters"""""""" retain the ability to reactivate and cause progressive disease when host immunity is suppressed. In the last five years, the investigators have developed systems for complementation, allelic exchange, and transposon mutagenesis. These systems have allowed them to identify the, previously unknown, targets of the drugs isoniazid, ethionamide, and ethambutol. They have also established a molecular basis for the attenuation of an M. bovis strain as due to an amino acid substitution in a principal sigma factor of RNA polymerase and have developed auxotrophic vaccine strains of BCG. They plan to extend these studies by using phage-based systems for transposon mutagenesis and allelic exchange to generate libraries of signature- tagged mutants of M. tuberculosis with the goal of identifying genes required for virulence and persistence. In addition, they plan to use the transposon system to probe the cell surface of M. tuberculosis by characterizing phage-resistance mechanisms and studying the secretion pathways. Ultimately, the knowledge of mycobacterial virulence and persistence factors should lead to the development of novel drugs, vaccines, and immunotherapies to control tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026170-13
Application #
6349784
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Sizemore, Christine F
Project Start
1988-12-01
Project End
2004-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
13
Fiscal Year
2001
Total Cost
$317,090
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Vilchèze, Catherine; Copeland, Jacqueline; Keiser, Tracy L et al. (2018) Rational Design of Biosafety Level 2-Approved, Multidrug-Resistant Strains of Mycobacterium tuberculosis through Nutrient Auxotrophy. MBio 9:
Harbut, Michael B; Yang, Baiyuan; Liu, Renhe et al. (2018) Small Molecules Targeting Mycobacterium tuberculosis Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity. Angew Chem Int Ed Engl 57:3478-3482
Tiwari, Sangeeta; van Tonder, Andries J; Vilchèze, Catherine et al. (2018) Arginine-deprivation-induced oxidative damage sterilizes Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 115:9779-9784
Vilchèze, Catherine; Kim, John; Jacobs Jr, William R (2018) Vitamin C Potentiates the Killing of Mycobacterium tuberculosis by the First-Line Tuberculosis Drugs Isoniazid and Rifampin in Mice. Antimicrob Agents Chemother 62:
Bhatt, Kiranmai; Machado, Henrique; Osório, Nuno S et al. (2018) A Nonribosomal Peptide Synthase Gene Driving Virulence in Mycobacterium tuberculosis. mSphere 3:
Yang, Yong; Thomas, Joseph; Li, Yunlong et al. (2017) Defining a temporal order of genetic requirements for development of mycobacterial biofilms. Mol Microbiol 105:794-809
Stratton, Thomas P; Perryman, Alexander L; Vilchèze, Catherine et al. (2017) Addressing the Metabolic Stability of Antituberculars through Machine Learning. ACS Med Chem Lett 8:1099-1104
Hanauer, David I; Graham, Mark J; SEA-PHAGES et al. (2017) An inclusive Research Education Community (iREC): Impact of the SEA-PHAGES program on research outcomes and student learning. Proc Natl Acad Sci U S A 114:13531-13536
Glass, Lisa N; Swapna, Ganduri; Chavadi, Sivagami Sundaram et al. (2017) Mycobacterium tuberculosis universal stress protein Rv2623 interacts with the putative ATP binding cassette (ABC) transporter Rv1747 to regulate mycobacterial growth. PLoS Pathog 13:e1006515
Saito, Kohta; Warrier, Thulasi; Somersan-Karakaya, Selin et al. (2017) Rifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations. Proc Natl Acad Sci U S A 114:E4832-E4840

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