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Faculty Profile

William R. Jacobs, Jr., Ph.D.

Dr. William R. Jacobs, Jr.

Professor, Department of Microbiology & Immunology

Professor, Department of Genetics

Investigator, Howard Hughes Medical Institute

 

Professional Interests

Extensively Drug Resistant Mycobacterium tuberculosis: The Death Defying Pathogen

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.

 

TB TERMINATOR

 

THE EXTERMINATORS

 

 

Selected Publications

 Selected Publications

  1. Wong, K-W., Jacobs, W.R. Jr. (2012) Mycobacterium tuberculosis exploits human interferon-γ to stimulate macrophage extracellular trap formation and necrosis. J Infect Dis. Submitted for publication – in revision.
  2. Vilcheze, C., Jacobs, W.R. Jr. (2012) The combination of sulfamethoxazole, trimethoprim, and Isoniazid or Rifampicin is bactericidal and prevents the emergence of drug resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother. in press
  3. Venkataswamy, M. M., M. F. Goldberg, A. Baena, J. Chan, W. R. Jacobs, Jr., and S. A. Porcelli. (2012) In vitro culture medium influences the vaccine efficacy of Mycobacterium bovis BCG. Vaccine 30:1038-49. PMCID PMC 3269512.
  4. Chapman, R., Shepard, E., Stutz, H., Douglass, N., Sambandamurthy, V., Garcia, I., Ryffel, B., Jacobs, W., Williamson, A. (2012) Priming with a Recombinant Pathtothenate Auxotroph of Mycobacterium bovis BCG and Boosting with MVA Elicits HIV-1 Gag Specific CD8+ TCells.  PLoS One, 7:3 e32769.  
  5. Goldberg, D. E., R. F. Siliciano, and W. R. Jacobs, Jr. (2012). Outwitting Evolution: Fighting Drug-Resistant TB, Malaria, and HIV. Cell 148:1271-83. PMCID PMC.
  6. McShane, H., W. R. Jacobs, P. E. Fine, S. G. Reed, D. N. McMurray, M. Behr, A. Williams, and I. M. Orme. (2012). BCG: Myths, realities, and the need for alternative vaccine strategies. Tuberculosis (Edinb) PMCID PMC 22349516
  7. Derrick, S. C., D. Dao, A. Yang, K. Kolibab, W. R. Jacobs, and S. L. Morris. (2012). Formulation of a mmaA4 Gene Deletion Mutant of Mycobacterium bovis BCG in Cationic Liposomes Significantly Enhances Protection against Tuberculosis. PLoS One 7:e32959. PMCID PMC 3307709.
  8. Jain, P., Hartman, T.,  Eisenberg, N., O'Donnell, M.R., Kriakov, J.,  Govender, K.,  Makume, M., Thaler, D., Hatfull, G.F., Sturm, A.W.,  Larsen, M.H., Moodley, P., Jacobs,W.R. Jr. (2012) ф2GFP10: A high-intensity fluorophage enables detection and rapid drug susceptibility testing of Mycobacterium tuberculosis directly from sputum samples. J Clin Microbiol 50:1362-9. PMCID PMC.
  9. Bourai, N., W. R. Jacobs, Jr., and S. Narayanan. (2012). Deletion and overexpression studies on DacB2, a putative low molecular mass penicillin binding protein from Mycobacterium tuberculosis H(37)Rv. Microb Pathog 52:109-16. PMCID PMC.
  10. Yamada, H., A. Bhatt, R. Danev, N. Fujiwara, S. Maeda, S. Mitarai, K. Chikamatsu, A. Aono, K. Nitta, W. R. Jacobs, Jr., and K. Nagayama. (2012). Non-acid-fastness in Mycobacteriumtuberculosis DeltakasB mutant correlates with the cell envelope electron density. Tuberculosis (Edinb) PMCID PMC.
  11. Yu, J. S., J. Whitesides, S. H. Lee, N. Taylor, W. R. Jacobs, Jr., N. L. Letvin, and B. F. Haynes. (2011). Flow cytometry sorting of recombinant mycobacterial species yields bacterial clones with enhanced insert expression. Clin Vaccine Immunol 18 (1):43-9.PMCID PMC3019783.
  12. Hinchey, J., B. Y. Jeon, H. Alley, B. Chen, M. Goldberg, S. Derrick, S. Morris, W. R. Jacobs, Jr., S. A. Porcelli, and S. Lee. (2011). Lysine auxotrophy combined with deletion of the SecA2 gene results in a safe and highly immunogenic candidate live attenuated vaccine for tuberculosis. PLoS One 6 (1):e15857.PMCID PMC3018466
  13. Rondon, L., M. Piuri, W. R. Jacobs, Jr., J. de Waard, G. F. Hatfull, and H. Takiff. (2011). Evaluation of Fluoromycobacteriophages for detecting drug resistance in Mycobacterium tuberculosis. J Clin Microbiol.49:1838-42.  PMCID PMC 3122682. 
  14. Prados-Rosales, R., A. Baena, L. R. Martinez, J. Luque-Garcia, R. Kalscheuer, U. Veeraraghavan, C. Camara, J. D. Nosanchuk, G. S. Besra, B. Chen, J. Jimenez, A. Glatman-Freedman, W. R. Jacobs, Jr., S. A. Porcelli, and A. Casadevall. (2011). Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice. J Clin Invest. PMCID PMC3069770.
  15. Xu, X., Vilcheze, C., Av-Gay, Y., Gomez-Velasco, A., and Jacobs, W.R. Jr., (2011) Precise Null Deletion Mutations of the Mycothiol Synthesis Genes Reveal Their Roll in Isoniazid and Ethionamide Resistance in Mycobacterium smegmatis. Antimicrob Agents Chemother. 55 (7):3133-9. PMCID PMC 3122461.
  16. Sweeney, K. A., D. N. Dao, M. F. Goldberg, T. Hsu, M. M. Venkataswamy, M. Henao-Tamayo, D. Ordway, R. S. Sellers, P. Jain, B. Chen, M. Chen, J. Kim, R. Lukose, J. Chan, I. M. Orme, S. A. Porcelli, and W. R. Jacobs, Jr. (2011). A recombinant Mycobacterium smegmatis induces potent bactericidal immunity against Mycobacterium tuberculosis. Nat Med 17:1261-8. PMCID PMC 3250071.
  17. Wong,K.W., and Jacobs,W.R. (2011) Critical role for NLRP3 in necrotic death triggered by M. tuberculosis. Cell Microbio. 13 (9):1371-84. PMCID PMC (In process).
  18. Vilchèze, C., Baughn, A.D., Tufariello, J., Leung,L., Kuo, M., Basler, C., Alland, D., Sacchettini, J.C., Freunlich, J.S., and Jacobs, W.R.Jr. (2011)  Novel inhibitors of InhA efficiently kill Mycobacterium tuberculosis under aerobic and anaerobic conditions. Antimicrob Agents Chemother. 55 (8):3889-98. PMCID  PMC 3147652.
  19. Sayahi, H., O. Zimhony, W. R. Jacobs, Jr., A. Shekhtman, and J. T. Welch. (2011). Pyrazinamide, but not pyrazinoic acid, is a competitive inhibitor of NADPH binding to Mycobacterium tuberculosis fatty acid synthase I. Bioorg Med Chem Lett. 21:4804-7. PMCID PMC.
  20. Pruksakorn, P., M. Arai, L. Liu, P. Moodley, W. R. Jacobs, Jr., and M. Kobayashi. (2011). Action-Mechanism of Trichoderin A, an Anti-dormant Mycobacterial Aminolipopeptide from Marine Sponge-Derived Trichoderma sp. Biol Pharm Bull 34 (8):1287-90. PMCID PMC (in process).
  21. Pope, W. H., C. M. Ferreira, D. Jacobs-Sera, R. C. Benjamin, A. J. Davis, R. J. DeJong, S. C. R. Elgin, F. R. Guilfoile, M. H. Forsyth, A. D. Harris, S. E. Harvey, L. E. Hughes, P. M. Hynes, A. S. Jackson, M. D. Jalal, E. A. MacMurray, C. M. Manley, M. J. McDonough, J. L. Mosier, L. J. Osterbann, H. S. Rabinowitz, C. N. Rhyan, D. A. Russell, M. S. Saha, C. D. Shaffer, S. E. Simon, E. F. Sims, I. G. Tovar, E. G. Weisser, J. T. Wertz, K. A. Weston-Hafer, K. E. Williamson, B. Zhang, S. G. Cresawn, P. Jain, M. Piuri, W. R. Jacobs, Jr., R. W. Hendrix, and G. F. Hatfull. (2011). Cluster K Mycobacteriophages: Insights into the Evolutionary Origins of Mycobacteriophage TM4. PLoS One 6:e26750. PMCID PMC 3203893.
  22. Chen, B., Weisbrod, T.R., Hsu, T., Sambandamurthy, V., Viera-Cruz, D., Chibbaro, A., Ghidoni, D., Kile, T., Barkley, W.E., Vilcheze, C., Colon-Berezin, C., Thaler, D., Larsen, M.H., Sturm, A.W., Jacobs. W.R. Jr.(2011) Einstein Contained Aerosol Pulmonizer (ECAP): Inproved Biosafety for Multi-Drug Resistant (MDR) and Extensively Drug Resistant (XDR) Mycobacterium tuberculosis Aerosol Infection Studies. Applied Biosafety 16 (3):134-138. PMCID PMC.
  23. Parra, M., S. C. Derrick, A. Yang, J. Tian, K. Kolibab, M. Oakley, L. P. Perera, W. R. Jacobs, S. Kumar, and S. L. Morris. (2011). Malaria Infections Do Not Compromise Vaccine-Induced Immunity against Tuberculosis in Mice. PLoS One 6:e28164. PMCID PMC. 3242757.
  24. Jain, P., D. S. Thaler, M. Maiga, G. S. Timmins, W. R. Bishai, G. F. Hatfull, M. H. Larsen, and W. R. Jacobs. (2011). Reporter phage and breath tests: emerging phenotypic assays for diagnosing active tuberculosis, antibiotic resistance, and treatment efficacy. J Infect Dis 204 Suppl 4:S1142-50. PMCID PMC 3247800.
  25. Vilcheze, C., Y. Av-Gay, S. W. Barnes, M. H. Larsen, J. R. Walker, R. J. Glynne, and W. R. Jacobs, Jr. (2011). Coresistance to isoniazid and ethionamide maps to mycothiol biosynthetic genes in Mycobacterium bovis. Antimicrob Agents Chemother 55:4422-3. PMCID PMC. 3165297.
  26. Vilcheze, C., B. Weinrick, K. W. Wong, B. Chen, and W. R. Jacobs, Jr. (2010). NAD+ auxotrophy is bacteriocidal for the tubercle bacilli. Mol Microbiol 76:365-77. PMCID PMC2945688.
  27. Vilcheze, C., Av-Gay, Y., Attarian, R., Liu, Z., Hazbon, M.H., Colangeli, R., Chen, B., Liu, W., Alland, D., Sacchettini, J.C., Jacobs, Jr., W.R.(2008) Mycothiol biosynthesis is essential for ethionamide susceptibility in Mycobacterium tuberculosis. Mol Microbiol. 69:1316-29. PubMed in process
  28. Dao, D. N., K. Lawrence, T. Hsu, I. P. Nascimento, D. Roshevsky, S. S. Gurcha, G. S. Besra, J., Chan, S. A. Porcelli, and W. R. Jacobs(2008)Repression of IL-12P40 is Controlled by MmaA4 Mediated Modification of Mycolic Acids Associated with Trehalose 6,6' Dimycolate. PLoS Pathogens.6:4(6):e1000081; 1-14. PMCID:2390761
  29. Mohamemohaideen, N.N., Palaninathan, S.K., Morin, P.M., Williams, B.J., Braunstein, M., Tichy, S.E., Locker, J., Russell, D.H., Jacobs, W.R., Jr., Sacchettini, J.C.(2008) Structure and Function of the Virulence-Associated High-Temperature Requirement A of Mycobacterium tuberculosis. Biochemistry [Epub ahead of print]
  30. Ojha, A.K., Baughn, A.D., Sambandan, D., Hsu, T., Trivellil, X., Guerardel, Y., Alahari, A., Kremer, L., Jacobs, W.R., Jr., Hatfull, G.F. (2008) Growth of Mycobacterium tuberculosis biofilms containing free mycolic acids and harboring drug tolerant bacteria. Mol. Microbiol. [Epub ahead of print]
  31. Bhatt, A., N. Fujiwara, K. Bhatt, S. Gurcha, L. Kremer, B. Chen, J. Chan, S. Porcelli, K. Kobayashi, G. Besra, and J. Jacobs, W.R. (2007)Deletion of kasB in Mycobacterium tuberculosis Causes a Loss of Acid-Fastness and Subclinical Latent Tuberculosis in Immunocompetent Mice. PNAS,USA 104:5157-5162.PMCID: PMC1829279
  32. Derrick, S., T. Evering, V. K. Sambandamurthy, K. V. Jalapathy, T. Hsu, B. Chen, M. Chen, R. Russell, A. P. Junqueira-Kipnis, I. M. Orme, S. Porcelli, J. Jacobs, W.R., and S. L. Morris(2006) Characterization of the Protective T Cell Response Generated in CD4 Deficient Mice By A Live Attenuated Mycobacterium tuberculosis Vaccine. Immunology 120:192-206.PMCID: PMC2265854
  33. Sambandamurthy, V.K., Derrick, S.C., Hsu, T., Chen, B., Larsen, M.H., Jalapathy, K.V., Chen, M., Kim, J., Porcelli, S.A., Chan, J., Morris, S.L., Jacobs, W.R. Jr. (2006)  Mycobacterium tuberculosis DRD1 DpanCD: A Safe and Limited Replicating Mutant Strain that Protects Immunocompetent and Immunocompromised Mice Against Experimental Tuberculosis. Vaccine 11:6309-6320.
  34. Vilchèze, C., Wang, F., Arai, M., Hazbòn, M.H., Colangeli, R., Kremer, L., Weisbrod, T.R., Alland, D., Sacchettini, J.C., Jacobs, W.R., Jr. (2006) Transfer of a Point Mutation in inhA Elucidates The Isoniazid Target in Mycobacterium tuberculosis. Nat. Med.12:1027-1029.
  35. Stover, C.K., V.F. de la Cruz, T.R. Fuerst, J.E. Burlein, L.A. Benson, L.T. Bennett, G.P. Gansal, J.F. Young, M.H. Lee, G.F. Hatfull, S.B. Snapper, R.G. Barletts, W.R. Jacobs, Jr. and B.R. Bloom (1991) New use of BCG for Recombinant Vaccines.  Nature  351:456-460. 
  36. Jacobs, Jr., W.R., R. Barletta, R. Udani, J. Chan, G. Kalkut, G. Sarkis, G.F. Hatfull and B.R. Bloom (1993) Rapid assessment of drug susceptibilities of Mycobacterium tuberculosis by means of luciferase reporter phages.  Science 260:819-822.
  37. Jacobs, Jr., W.R., M. Tuckman, and B.R. Bloom (1987) Introduction of foreign DNA into mycobacteria using a shuttle phasmid.  Nature  327:532-536.

 

 

More Information About Dr. William Jacobs, Jr.

TB Vaccine Research Group

HHMI Investigators

Material in this section is provided by individual faculty members who are solely responsible for its accuracy and content.

Contact

Albert Einstein College of Medicine
Michael F. Price Center
1301 Morris Park Avenue , Room 555
Bronx, NY 10461

Tel: 718.678.1075
Fax: 718.678.1085
william.jacobs@einstein.yu.edu

 
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Media Coverage

The American Association for the Advancement of Science features Dr. William Jacobs, Jr., dubbed the “TB Terminator,” on its “Member Spotlight” blog.

TheScientist features an inexpensive new test developed by Dr. William Jacobs, Jr., and a team of researchers that quickly detects tuberculosis and determines whether it is drug resistant, a process that currently takes months and may result in death.

More media coverage