Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI091790-03
Application #
8414837
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
2012-12-01
Budget End
2013-11-30
Support Year
3
Fiscal Year
2013
Total Cost
$569,199
Indirect Cost
$126,049

  Institution

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

  Publications

Tiwari, Divya; Park, Sae Woong; Essawy, Maram M et al. (2018) Targeting protein biotinylation enhances tuberculosis chemotherapy. Sci Transl Med 10:
Liu, Feng; Dawadi, Surendra; Maize, Kimberly M et al. (2017) Structure-Based Optimization of Pyridoxal 5'-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis. J Med Chem 60:5507-5520
Eiden, Carter G; Aldrich, Courtney C (2017) Synthesis of a 3-Amino-2,3-dihydropyrid-4-one and Related Heterocyclic Analogues as Mechanism-Based Inhibitors of BioA, a Pyridoxal Phosphate-Dependent Enzyme. J Org Chem 82:7806-7819
Eiden, Carter G; Maize, Kimberly M; Finzel, Barry C et al. (2017) Rational Optimization of Mechanism-Based Inhibitors through Determination of the Microscopic Rate Constants of Inactivation. J Am Chem Soc 139:7132-7135
Bockman, Matthew R; Kalinda, Alvin S; Petrelli, Riccardo et al. (2015) Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors. J Med Chem 58:7349-7369
Ehrt, Sabine; Rhee, Kyu; Schnappinger, Dirk (2015) Mycobacterial genes essential for the pathogen's survival in the host. Immunol Rev 264:319-26
Dai, Ran; Geders, Todd W; Liu, Feng et al. (2015) Fragment-based exploration of binding site flexibility in Mycobacterium tuberculosis BioA. J Med Chem 58:5208-17
Park, Sae Woong; Casalena, Dominick E; Wilson, Daniel J et al. (2015) Target-based identification of whole-cell active inhibitors of biotin biosynthesis in Mycobacterium tuberculosis. Chem Biol 22:76-86
Dai, Ran; Wilson, Daniel J; Geders, Todd W et al. (2014) Inhibition of Mycobacterium tuberculosis transaminase BioA by aryl hydrazines and hydrazides. Chembiochem 15:575-86
Schnappinger, Dirk; Ehrt, Sabine (2014) Regulated Expression Systems for Mycobacteria and Their Applications. Microbiol Spectr 2:

Showing the most recent 10 out of 16 publications