My primary research interest is mechanisms of drug resistance and persistence in Mycobacterium tuberculosis. Drug-resistant TB (MDR-TB, XDR-TB) is an increasing public health problem and poses a significant threat to the disease control. One third of the world population is latently infected with the tubercle bacillus and HIV infection threatens to allow the latent TB to reactivate and worsen the TB situation. Improved understanding of the persistence of tubercle bacillus and the mechanisms of drug resistance, devising more rapid diagnostic tools, as well as developing drugs and vaccines that are active against drug-resistant and persister bacteria are important for better control of TB. For more details, see http://magazine.jhsph.edu/2007/Spring/features/patient_scientist/

We also have international collaborative projects in China to study (1) how MDR-TB/XDR-TB emerges in the field, including analysis of both host and bacterial factors involved and how a peculiar form of rifampin-dependent/enahnced MDR-TB develops and trasmits in patients; (2) rapid molecular diagnostic tests and vaccine development; (3)cancer stem cells from patient specimens;

Areas of Interest:

1. Mechanisms of persister drug pyrazinamide (PZA) action and resistance in M. tuberculosis

2. Mechanisms of bacterial persistence and L-forms

3. Mycobacterial pathogenesis

4. Development of novel drugs and vaccines targeting persister bacteria

5. Development of novel diagnostic tools for improved detection of TB and drug-resistant TB

6. Cancer stem cell mechanisms and drugs

Molecular Microbiology and Immunology, tuberculosis, mycobacteria, drug resistance, isoniazid, pyrazinamide, dormancy, persistence, L-form bacteria, drug and vaccine development, cancer stem cells

Selected Publications:

Min Zhong, Xi-yan Zhang, Yiwei Wang, Chun-zhi Zhang, Gang Chen, Pin-pin Hu, Miao Li, Bingdong Zhu, Wenhong Zhang, Ying Zhang. 2009. An interesting case of rifampin-dependent/enhanced MDR-TB. Int J Tuberc Lung Dis. In press.

Zhang Y. and Yew WW. (2009). Mechanisms of Drug Resistance in Mycobacterium tuberculosis,

State of the Art. Int J Tuberc Lung Dis. 13:1320-30.

Glover W, Yang Y, Zhang Y. (2009). Insights into the Molecular Basis of L-Form Formation and Survival in Escherichia coli. PLoS ONE. 4(10): e7316. (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0007316)

Zheng H, Lu L, Wang B, Pu S, Zhang X, Zhu G, Shi W, Zhang L, Wang H, Wang S, Zhao G, Zhang Y. (2008). Comparative Genomic Analysis of Attenuated Mycobacterium tuberculosis Strain H37Ra versus its Virulent Counterpart H37Rv: Insight into the Basis of Virulence Attenuation. PLoS ONE, 3(6): e2375.

Zhang, Y and Jacobs, WR, Jr (2008). Molecular mechanisms of drug resistance of M. tuberculosis. In Tuberculosis Handbook, Volume 1, E. Rubin and S.H.E. Kaufman, Ed, Wiley-VCH. p321-376.

Zhou, J and Zhang, Y. (2008). Cancer Stem Cells: Models, Mechanisms, and Implications for Improved Treatment. Cell Cycle, 7: 1360-1370.

Zhou J, Zhang H, Gu P, Bai J, Margolick JB, Yin D, and Zhang Y. (2008). Cancer stem/progenitor cell active compound 8-quinolinol in combination with paclitaxel achieves an improved cure of breast cancer in the mouse model. May 28. [Epub ahead of print]

Zhou J, Wulfkuhle J, Zhang H, Gu P, Yang Y, Deng J, Margolick JB, Liotta LA, Petricoin E 3rd, Zhang Y. (2007). Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci U S A. 2007 Oct 2; [Epub ahead of print]

Zhang, Y. (2007). Advances in the Treatment of Tuberculosis. Clin Pharmacol Ther 82:595-600

Li, Y. and Y. Zhang. (2007). PhoU is a persistence switch involved in persister formation and tolerance to multiple antibiotics and stresses in Escherichia coli. Antimicrob. Agents Chemother. 51:2092-9

Byrne, ST, Denkin, SM, Zhang, Y. (2007). Aspirin and ibuprofen enhance pyrazinamide treatment of murine tuberculosis. J. Antimicrob Chemother. 59: 313-316.

Wade, MM, and Zhang, Y. (2006). Effect of Weak Acids, UV and Proton Motive Force Inhibitors on

Pyrazinamide Activity against Mycobacterium tuberculosis in vitro. J. Antimicrob. Chemother. 58: 936-941.

Zhang, Y. (2005). The Magic Bullets and Tuberculosis Drug Targets. Ann. Rev. Pharmacol. Toxicol. 45: 529-564.

Zhang, Y. (2004). Persistent and Dormant Tubercle Bacilli and Latent Tuberculosis. Frontiers in Bioscience. 9: 1136-1156.

Zhang, Y. (2004). Isoniazid, In William N. Rom and Stuart Garay, ed, TUBERCULOSIS – 2nd Ed, Chapter 49, pp739-758, Lippincott Williams & Wilkins, A Wolters Kluwer Company, New York.

Zhang, Y. and D.A. Mitchison (2003). The curious characteristics of pyrazinamide: a review. Int J Tuberc Lung Dis, 7:6-21.

Zhang, Y., M. M. Wade, A. Scorpio, H. Zhang,, Z. Sun (2003). Mode of Action of Pyrazinamide: Disruption of Mycobacterium tuberculosis Membrane Transport and Energetics by Pyrazinoic Acid. J. Antimicrob. Chemother. 52: 790-795.

Sun, Z., and Zhang, Y. (1999). Spent culture supernatant of Mycobacterium tuberculosis strain H37Ra improved the viability of aged cultures and allowed small inocula to initiate growth in liquid culture. J. Bacteriol. 181:7626-7628.

Zhang, Y., Scorpio, A., Nikaido, H., and Sun, Z.H. (1999). Role of acid pH and deficient efflux of pyrazinoic acid in the unique susceptibility of Mycobacterium tuberculosis to pyrazinamide. J. Bacteriol. 181:2044-2049.

Scorpio, A. and Zhang, Y. (1996) Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus [Comment]. Nature Med 2:662-667.

Zhang, Y., Heym, B., Allen, B., Young, D., and Cole, S. (1992) The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. [Comment] Nature (London) 358: 591-593.