The tuberculosis epidemic remains poorly controlled in part because of the rise of drug resistance and the lack of new drugs.  A significant challenge is the identification and validation of novel in vivo targets that can be chemically disrupted.  Here we describe our investigations using whole cell screening of a diverse collection of small molecules as a methodology for identifying novel inhibitors that target new pathways for Mycobacterium tuberculosis drug discovery.   We have identified several new inhibitors that target distinct steps in mycobacterial cell wall biosynthesis, including a class of 6-aryl-5,7-dimethyl-4-phenylcoumarin compounds that kills drug resistant and drug sensitive Mycobacterium tuberculosis by inhibiting the novel target FadD32, a crucial enzyme for mycolic acid biosynthesis. The most promising inhibitor of this class is effective in two animal models of mycobacterial infection.  In addition we describe novel inhibitors that target the cell wall with efficacy in models of active and latent tuberculosis.

Identification and validation of new therapeutic targets in <i>M. tuberculosis</i> cell wall biosynthesis using whole cell based high-throughput screening

245th National Meeting (2013)

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Identification and validation of new therapeutic targets in M. tuberculosis cell wall biosynthesis using whole cell based high-throughput screening