Tuberculosis (TB) remains the second leading cause of human death from a single infectious agent. Mycobacterium tuberculosis strains that are resistant against multiple drugs (MDR) or are extremely drug resistant (XDR) continue to emerge and spread. New drugs are needed limit the impact of TB on global public health. We demonstrated that biotin metabolism is essential for growth and persistence of M. tuberculosis during infections, that biotin starvation can cause bacterial cell death, and we identified inhibitors of the biotin protein ligase of M. tuberculosis. In the proposed research we will (i) measure vulnerability of M. tuberculosis towards inhibition of different enzymes participating in biotin metabolism, (ii) identify triggers of biotin-starvation-induced cell death in M. tuberculosis, (iii) use structure-based drug design to further develop available lead compounds that inhibit biotin metabolism in M. tuberculosis, and (iv) study the mechanism of action of these inhibitors.

Public Health Relevance

Tuberculosis (TB) is the world's second leading cause of premature human death from an infectious disease. Work outlined in this proposal will directly contribute to the development of new TB drugs and ultimately help reducing the impact of this disease on global health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI091790-04
Application #
8586248
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Boyce, Jim P
Project Start
2010-12-03
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$544,977
Indirect Cost
$120,685
Name
Weill Medical College of Cornell University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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Schnappinger, Dirk; Ehrt, Sabine (2014) Regulated Expression Systems for Mycobacteria and Their Applications. Microbiol Spectr 2:
Shi, Ce; Tiwari, Divya; Wilson, Daniel J et al. (2013) Bisubstrate Inhibitors of Biotin Protein Ligase in Mycobacterium tuberculosis Resistant to Cyclonucleoside Formation. ACS Med Chem Lett 4:
Duckworth, Benjamin P; Geders, Todd W; Tiwari, Divya et al. (2011) Bisubstrate adenylation inhibitors of biotin protein ligase from Mycobacterium tuberculosis. Chem Biol 18:1432-41
Wilson, Daniel J; Shi, Ce; Duckworth, Benjamin P et al. (2011) A continuous fluorescence displacement assay for BioA: an enzyme involved in biotin biosynthesis. Anal Biochem 416:27-38
Shi, Ce; Geders, Todd W; Park, Sae Woong et al. (2011) Mechanism-based inactivation by aromatization of the transaminase BioA involved in biotin biosynthesis in Mycobaterium tuberculosis. J Am Chem Soc 133:18194-201