Abstract

This project describes the systematic development of antimycobacterial agents targeting the unique nature of the lipid components of the bacterial cell wall. The approaches are designed specifically to inhibit the activities of the b-keto-acyl-synthases which generate the long chain fatty acids. The strategy is based on the natural product lead compounds cerulinin and thiolactomycin both of which show activity against FAS I and II activities, and are active against M.avium and M. tuberculosis in vitro. Generation of synthetic analogues has lead to the identification of compound III-50 which shows activity both in vitro and in in vivo murine TB.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043846-05
Application #
6511073
Study Section
AIDS and Related Research Study Section 5 (ARRE)
Program Officer
Near, Karen A
Project Start
1998-08-01
Project End
2003-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
5
Fiscal Year
2002
Total Cost
$306,611
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Lun, Shichun; Miranda, David; Kubler, Andre et al. (2014) Synthetic lethality reveals mechanisms of Mycobacterium tuberculosis resistance to ?-lactams. MBio 5:e01767-14
Olaleye, Omonike; Raghunand, Tirumalai R; Bhat, Shridhar et al. (2011) Characterization of clioquinol and analogues as novel inhibitors of methionine aminopeptidases from Mycobacterium tuberculosis. Tuberculosis (Edinb) 91 Suppl 1:S61-5
Olaleye, Omonike; Raghunand, Tirumalai R; Bhat, Shridhar et al. (2010) Methionine aminopeptidases from Mycobacterium tuberculosis as novel antimycobacterial targets. Chem Biol 17:86-97
Parrish, Nicole M; Ko, Chiew G; Dick, James D (2009) Activity of DSA against anaerobically adapted Mycobacterium bovis BCG in vitro. Tuberculosis (Edinb) 89:325-7
Ahmad, Zahoor; Klinkenberg, Lee G; Pinn, Michael L et al. (2009) Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, Mycobacterium tuberculosis in the guinea pig. J Infect Dis 200:1136-43
Be, Nicholas A; Lamichhane, Gyanu; Grosset, Jacques et al. (2008) Murine model to study the invasion and survival of Mycobacterium tuberculosis in the central nervous system. J Infect Dis 198:1520-8
Klinkenberg, Lee G; Sutherland, Lesley A; Bishai, William R et al. (2008) Metronidazole lacks activity against Mycobacterium tuberculosis in an in vivo hypoxic granuloma model of latency. J Infect Dis 198:275-83
Lee, Jong-Hee; Karakousis, Petros C; Bishai, William R (2008) Roles of SigB and SigF in the Mycobacterium tuberculosis sigma factor network. J Bacteriol 190:699-707
Nuermberger, Eric; Tyagi, Sandeep; Tasneen, Rokeya et al. (2008) Powerful bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother 52:1522-4
Abdul-Majid, Khairul-Bariah; Ly, Lan H; Converse, Paul J et al. (2008) Altered cellular infiltration and cytokine levels during early Mycobacterium tuberculosis sigC mutant infection are associated with late-stage disease attenuation and milder immunopathology in mice. BMC Microbiol 8:151

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