Abstract

The focus of this proposal is to extend the recently developed genetic systems that permit gene transfer in mycobacterial species in order to define genes responsible for the virulence of N. tuberculosis. Transposon mutagenesis systems will be developed for N. tuberculosis and BCG in order to generate libraries of insertional mutations. Homologous recombination has not been possible in M. tuberculosis and so strains and systems will be developed that permit the specific genetic engineering of M. tuberculosis. Novel screening systems will also be developed to identify the genes of M. tuberculosis that are induced when the bacilli are grown in animal hosts. The nature of the mutations that attenuate the well- characterized BCG strains and the M. tuberculosis H37Ra strain will be investigated using both genetic transfer and genomic mismatch scanning strategies. This work may provide the basis for defining virulence and drug resistance determinants of M. tuberculosis as well as the means for engineering novel tuberculosis vaccines.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026170-07
Application #
2063267
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1988-12-01
Project End
1998-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
7
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

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

  Publications

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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