In HIV-positive individuals, the chances of reactivation of tuberculosis (TB) infection, failure of active TB disease or relapse are higher than in immune competent populations. Anti-TB chemotherapy must fully sterilize all infection sites given the cytokine dysregulation and global immune perturbations. Pyrazinamide (PZA) is a mainstay of nearly all chemotherapies for drug-sensitive and drug-resistant tuberculosis (TB) and only TB drug capable of accelerating the sterilization of most forms of TB. Despite its therapeutic importance, we lack knowledge of its biodistribution within and among affected lesions, as well as the fates and actions of PZA both at these sites and within the mycobacterium itself. The extensive heterogeneity of TB lesions, in terms of drug penetration, pathophysiology, and susceptibility of the bacilli, is considered a major cause of persistence leading to relapse or reactivation. To achieve the next 'quantum leap'in TB control programs and effectively prevent TB activation in HIV patient populations, we must design drug regimens made of antibiotics that have complementary distribution in the various niches where bacilli are found within granulomas. The focus on PZA to develop shorter and more effective therapies for TB-HIV stems from our observations that several drug classes diffuse poorly or not at all into necrotic tissues and caseum, while PZA appears to accumulate preferentially in this niche where persisters are suspected to reside. We take advantage of the rabbit models of chronic cavitary and latent TB, which together recapitulate the spectrum of human pulmonary lesions, to expand our mechanistic understanding of PZA's unique sterilizing activity. We have recently developed and applied imaging mass spectrometry and intrabacterial metabolomic platforms with Mycobacterium tuberculosis (Mtb) to measure the lesion-specific distribution and bio- activation of PZA, and discovered previously unsuspected fates of PZA that may contribute to its sterilizing properties. The specific goals of this proposal are (1) to define the biodistribution and metabolic fate of PZA as it transits from the gastrointestinal tract, to the center of necrotic granulomas where its target bacterial population, to its molecular targets within Mtb itself, and (2) to asses the potential of PZA in killing specific bacterial populations suspected of being involved in relapse, reactivation of latent TB, cavitary disease progression, and disease transmission. We propose to conduct lesion-centric PK-PD studies with human-equivalent doses of PZA in the latent and progressive cavitary rabbit models. Combined data of penetration and bactericidal activities in specific lesions will inform the rational design of future drug regimens containing PZA as well as the most effective timing of PZA therapy against TB-HIV.

Public Health Relevance

To rationally design optimal drug regimens that will effectively prevent tuberculosis (TB) activation in HIV patient populations, new anti-TB drug regimens that have improved sterilizing properties are required. The proposed studies seek to provide pharmacokinetic and pharmacodynamic interpretation of the unique sterilizing effect of pyrazinamide. A better understanding of pyrazinamide's contribution to anti-TB therapy and its synergistic properties will inform the design and development of complementary drug combinations against TB-HIV co-infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI106398-01A1
Application #
8603472
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Srinivasan, Sudha
Project Start
2013-08-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$771,638
Indirect Cost
$245,833
Name
Rutgers University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
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Chen, Chao; Gardete, Susana; Jansen, Robert Sander et al. (2018) Verapamil Targets Membrane Energetics in Mycobacterium tuberculosis. Antimicrob Agents Chemother 62:
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Lanoix, Jean-Philippe; Tasneen, Rokeya; O'Brien, Paul et al. (2016) High Systemic Exposure of Pyrazinoic Acid Has Limited Antituberculosis Activity in Murine and Rabbit Models of Tuberculosis. Antimicrob Agents Chemother 60:4197-205
Sarathy, Jansy P; Zuccotto, Fabio; Hsinpin, Ho et al. (2016) Prediction of Drug Penetration in Tuberculosis Lesions. ACS Infect Dis 2:552-63

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