Each year, Mycobacterium tuberculosis infections contribute to over 8 million new cases of tuberculosis (TB) and nearly 2 million deaths. Pyrazinamide (PZA) is a first-line sterilizing anti-tubercular drug that is anticipated to be an irreplaceable component of future TB treatment regimens. Despite more than 60 years of clinical use of PZA, the mechanistic basis for its activity has yet to be resolved. Previous studie have demonstrated that PZA is a pro-drug that is converted to the active form of pyrazinoic acid (POA) by the M. tuberculosis amidase PncA, and that loss of function mutations in pncA account for the vast majority of PZA resistance. In addition, while PZA is only conditionally bacteriostatic for M. tuberculosis in laboratory culture, this drug mediates sterilization of bacili in humans and in animal models of infection. Thus, there is an as yet undefined host-dependent activity involved in potentiation of PZA action on M. tuberculosis. Our long-term goal for this project is to define the mechanistic basis for PZA action against M. tuberculosis. It is known that POA, but not PZA, forms complexes with several divalent metals involved in biocatalysis and oxidative stress, yet the relevance of this interaction for PZA action has not been explored. We are using a multidisciplinary approach to address the hypothesis that PZA treatment has a profound impact on metal homeostasis and oxidative stress in M. tuberculosis. These studies will shed new light on the poorly understood mode of action of PZA and stand to explain the dichotomous outcome of M. tuberculosis PZA exposure in culture versus in a mammalian system. Resolving the basis for PZA action will guide the discovery of novel agents with a conserved or improved action against M. tuberculosis to counter drug resistance.

Public Health Relevance

Pyrazinamide is a critical first-line drug used in the treatment of Mycobacterium tuberculosis infections. Our effective tuberculosis drug arsenal is being invalidated by the ongoing spread of drug resistant strains of M. tuberculosis. The focus of this project is to determine the basis for the anti-tubercular action of pyrazinamide which will enable the discovery of new drugs with a conserved action to counter drug resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI123146-02
Application #
9212104
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Boyce, Jim P
Project Start
2016-02-01
Project End
2021-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
2
Fiscal Year
2017
Total Cost
$381,458
Indirect Cost
$131,458
Name
University of Minnesota Twin Cities
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Dillon, Nicholas A; Peterson, Nicholas D; Feaga, Heather A et al. (2017) Anti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA. Sci Rep 7:6135
Rosen, Brandon C; Dillon, Nicholas A; Peterson, Nicholas D et al. (2017) Long-Chain Fatty Acyl Coenzyme A Ligase FadD2 Mediates Intrinsic Pyrazinamide Resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 61:
Alumasa, John N; Manzanillo, Paolo S; Peterson, Nicholas D et al. (2017) Ribosome Rescue Inhibitors Kill Actively Growing and Nonreplicating Persister Mycobacterium tuberculosis Cells. ACS Infect Dis 3:634-644