Pyrazinamide (PZA) is an important frontline tuberculosis (TB) drug that is involved in shortening the TB therapy. PZA is an unconventional and paradoxical drug. Despite its powerful sterilizing activity in vivo and its importance in achieving the short course therapy, PZA has no activity against M. tuberculosis under normal culture conditions but is active at acid pH, and PZA kills nongrowing bacilli more effectively than actively growing bacilli. The recent interest to develop new TB drugs that can shorten the therapy has highlighted the importance to understand the mode of action of PZA. Although PZA has been used in clinical treatment of TB since 1952 -the same year as INH, its mode of action is the least understood of all TB drugs because of the paradoxical nature of PZA. Work from this laboratory supported by this application has resulted in a number of significant findings about the mode of action of PZA. Based on these observations, we hypothesize that pyrazinoic acid (POA), the active form of PZA, targets the membrane and interferes with membrane energetics. In this application, we propose the following specific aims to further our understanding of this important TB drug: (1) To investigate the effect of factors that affect membrane energy metabolism on the activity of PZA/POA against M. tuberculosis. These factors include: low oxygen, weak acids, starvation, respiratory chain enzymes and aconitase (2) To assess the effect of enhancers of PZA activity on further improving the sterilizing activity of PZA against M. tuberculosis in vivo in mice, (3) To identify new mechanisms of PZA action and resistance by comparing the gene expression profiles of resistant strains without pncA mutations with sensitive strain in response to PZA. These studies will improve our understanding of mechanisms of PZA action and resistance and should have implications for the design of new antituberculosis drugs that can shorten the TB therapy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-DDR (01))
Program Officer
Sizemore, Christine F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Public Health
United States
Zip Code
Shi, Wanliang; Zhang, Xuelian; Jiang, Xin et al. (2011) Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science 333:1630-2
Shi, Wanliang; Zhang, Ying (2010) PhoY2 but not PhoY1 is the PhoU homologue involved in persisters in Mycobacterium tuberculosis. J Antimicrob Chemother 65:1237-42
Zhong, M; Zhang, X; Wang, Y et al. (2010) An interesting case of rifampicin-dependent/-enhanced multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 14:40-4
Chen, Lin; Shi, Wanliang; Li, Hui et al. (2010) Critical role of toll-like receptor 9 in morphine and Mycobacterium tuberculosis-Induced apoptosis in mice. PLoS One 5:e9205
Dheda, Keertan; Schwander, Stephan K; Zhu, Bingdong et al. (2010) The immunology of tuberculosis: from bench to bedside. Respirology 15:433-50
Ma, Chao; Sim, Shuzhen; Shi, Wanliang et al. (2010) Energy production genes sucB and ubiF are involved in persister survival and tolerance to multiple antibiotics and stresses in Escherichia coli. FEMS Microbiol Lett 303:33-40
Zhang, Guoping; Zhu, Bingdong; Shi, Wanliang et al. (2010) Evaluation of mycobacterial virulence using rabbit skin liquefaction model. Virulence 1:156-63
Sheen, Patricia; Mendez, Melissa; Gilman, Robert H et al. (2009) Sputum PCR-single-strand conformational polymorphism test for same-day detection of pyrazinamide resistance in tuberculosis patients. J Clin Microbiol 47:2937-43
Jiang, Xin; Lu, Chanyi; Gao, Feng et al. (2009) A rapid and simple method for identifying Mycobacterium tuberculosis W-Beijing strains based on detection of a unique mutation in Rv0927c by PCR-SSCP. Microbes Infect 11:419-23
Zhou, Jiangbing; Zhang, Hao; Gu, Peihua et al. (2009) Cancer stem/progenitor cell active compound 8-quinolinol in combination with paclitaxel achieves an improved cure of breast cancer in the mouse model. Breast Cancer Res Treat 115:269-77

Showing the most recent 10 out of 48 publications