Tuberculosis, caused by Mycobacterium tuberculosis, causes one in four avoidable deaths in the Third World and kills more adults than malaria, AIDS, and all tropical diseases combined. In recent years, there have been dramatic increases in the numbers of new cases worldwide - one of the consequences of the AIDS epidemic. In addition to these increasing incidences, there has been an emergence of M. tuberculosis strains that are resistant to all seven anti-tuberculosis agents. These alarming trends have caused the World Health Organization to declare tuberculosis a global health emergency, a distinction never accorded another disease. My laboratory has focused its efforts on developing systems to genetically manipulate mycobacteria, particularly M. tuberculosis. These tools have allowed us to: 1) develop the luciferase reporter phage assay for rapid assessment of drug susceptibilities, 2) analyze the genes involved in resistance to tuberculosis drugs such as isoniazid, ethionamide, and etyhambutol, and 3) to identify specific phenotypic properties associated with a tuberculosis pathogenesis. Current research efforts are aimed at identifying genes involved in the virulence of M. tuberculosis, identifying novel drug targets, generating rapid and robust phage diagnostics for drug resistant strains of M. tuberculosis, and engineering attenuated mutants of M. tuberculosis and other mycobacteria that can be used as live-cell tuberculosis vaccines.
1. Vilchèze, C., Hartman, T., Weinrick, B., and Jacobs, W.R. (2013). Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction. Nat. Commun 4:1881. (PMCID in process).
2. Wilson, R., P. Kumar, V. Parashar, C. Vilcheze, R. Veyron-Churlet, J. S. Freundlich, S. W. Barnes, J. R. Walker, M. J. Szymonifka, E. Marchiano, S. Shenai, R. Colangeli, W. R. Jacobs, Jr., M. B. Neiditch, L. Kremer, and D. Alland. (2013). Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis. Nat Chem Biol.
3. Chege, G.K., Burgers, W.A., Stutz, H., Meyers, A., Chapman, R., Kiravu, A., Bunjun, R., Shephard, E.G., Jacobs, W.R., Rybicki, E., Williamson, A. (2013) Robust immunity to a auxotrophic BCG-VLP prime-boost HIV vaccine candidate in a non-human primate model. J Virol 87 (9):5151-60. PMCID: PMC3624307.
4. Jain, P., Hsu, T., Arai, M., Biermann, K. E., Thaler, D. S., Nguyen, A., Gonzalez, P., Ratner, H., Kriakov, J. Chen, B., Larsen, M. H., Jacobs Jr, W. R., Jr. (2013) Specialized Transduction Designed for Precise High throughput Deletions in Mycobacterium tuberculosis. PLoS Genet (submitted).
5. Cheshenko, N., Trepanier,J.B., Stefanidou, M., Buckley, N., Gonzalez, P., Jacobs,W., Herold, B.C. (2013) HSV Activates Akt to Trigger Calcium Release and Promote viral entry: Novel candidate target for treatment and suppression. FASEB (accepted).
6. Anderson, J. W., D. Sarantakis, J. Terpinski, T. R. Santha Kumar, H. C. Tsai, M. Kuo, A. L. Ager, W. R. Jacobs, Jr., G. A. Schiehser, S. Ekins, J. C. Sacchettini, D. P. Jacobus, D. A. Fidock, and J. S. Freundlich. (2013). Novel diaryl ureas with efficacy in a mouse model of malaria. Bioorg Med Chem Lett 23:1022-5.(PMCID PMC in process).
7. Lim, L. E., C. Vilcheze, C. Ng, W. R. Jacobs, Jr., S. Ramon-Garcia, and C. J. Thompson. (2013). Anthelmintic Avermectins Kill Mycobacterium tuberculosis, Including Multidrug-Resistant Clinical Strains. Antimicrob Agents Chemother 57:1040-6. PMCID PMC 3553693.
8. Wilson, R., Kumar, P., Parashar, V., Vilchèze, C., Veyron-Churlet, R., Freundlich, J.S., Barnes, W., Walker, J.R., Marchiano, E., Shenai, S., Colangeli, R., Jocobs, W.R., Jr., Neiditch, M.B., Kremer, L., Alland, D. (2012) Pks13 is required for mycolic acid biosynthesis in Mycobacterium tuberculosis and is specifically inhibited by a novel class of thiophene compounds. (submitted).
9. Wang,F., Sambandan, D., Halder, R., Wang, J., Batt, S., Weinrick, B.C., Ahmad, I., Yang, P., Zhang, Y., Kim, J.,Hassani, M., Huszar, S., Trefzer, C., Ma, Z., Kaneko, T., Mdluli, K.E., Franzblau, S.c Chatterjee, A., Johnsson, K., Mikusova, K., Besra, G., Fütterer, K., Jacobs,W.R., Jr. Schultz, P.G. (2013) Identification of a Small Molecule with Activity against Drug-resistant and Persistent Tuberculosis. PNAS (in press).
10. Miallau, L., P. Jain, M. A. Arbing, D. Cascio, T. Phan, C. J. Ahn, S. Chan, I. Chernishof, M. Maxson, J. Chiang, W. R. Jacobs, Jr., and D. S. Eisenberg. (2013). Comparative proteomics identifies the cell-associated lethality of M. tuberculosis RelBE-like toxin-antitoxin complexes. Structure 21 (4):627-37. (PMCID in process).
11. Sambandan, D., Dao, D.N., Weinrick, B.C., Vilcheze, C., Grucha, S.S., Ojha, A., Kremer, L., Besra, G.S., Hatfull, G.F., Jacobs, W.R. (2013) Keto-Mycolic acid-dependent pellicle formation confers tolerance to drug-sensitive Mycobacterium tuberculosis. Mbio. 4(3). PMCID: PMC3663190.
12. Wong, K-W., Jacobs, W.R. Jr. (2013) Mycobacterium tuberculosis exploits human interferon-γ to stimulate macrophage extracellular trap formation and necrosis. J Infect Dis 208 (1):109-19 PMCID PMC3666134.
13. Weinrick, B., Vilchèze,C., Chen, B., Kim, J., Chen, M., Larsen, M.H., Jacobs, W.R.,Jr.(2013)Principles and Practices for Safe Manipulation of Pathogenic Mycobacteria in a BSL-3 Environment Part 2. J Vis EXP. (Submitted).
14. Vilchèze,C., Weinrick, B., Chen, B., Kim, J., Chen, M., Larsen, M.H., Jacobs, W.R.,Jr.(2013)Principles and Practices for Safe Manipulation of Pathogenic Mycobacteria in a BSL-3 Environment Part 3. J Vis EXP. (Submitted).
15. Sayahi, H., K. M. Pugliese, O. Zimhony, W. R. Jacobs, Jr., A. Shekhtman, and J. T. Welch. (2012). Analogs of the Antituberculous Agent Pyrazinamide Are Competitive Inhibitors of NADPH Binding to M. tuberculosis Fatty Acid Synthase I. Chem Biodivers 9:2582-96. PMCID PMC.
16. Ly, D., Kasmar, A.G., Cheng, T., DeJong, A., Huang, S., Roy, S., Bhatt, A., van Summeren, R.R., Altman, J.D., Jacobs, W.R., Adams, E.J., Minnaard, A. J., Porcelli, S.A., Moody, D.B. (2012) CD1c tetramers and sicovery of M. tuberculosis phosphomycoketides reveal cellular antigen processing for the human CD1c system. J Exp Med 210 (4):729-41. PMCID: PMC3620358.
17. Jensen, K., U. D. Ranganathan, K. K. Van Rompay, D. R. Canfield, I. Khan, R. Ravindran, P. A. Luciw, W. R. Jacobs, Jr., G. Fennelly, M. Larsen, and K. Abel. (2012). A recombinant attenuated Mycobacterium tuberculosis vaccine strain is safe in immunosuppressed SIV-infected infant macaques. Clin Vaccine Immunol PMCID PMC 3416096.
More Information About Dr. William Jacobs, Jr.
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Albert Einstein College of Medicine
Michael F. Price Center
1301 Morris Park Avenue , Room 555
Bronx, NY 10461
Science News interviews Dr. Betsy Herold about her new research with Dr. Bill Jacobs on an experimental herpes vaccine.
In a Nautilus profile, Dr. William Jacobs, Jr., discusses the key breakthroughs in his tuberculosis research and how losing his vision impacted his career path.