Mycobacterium tuberculosis ClpC1: A potential target for tuberculosis drug discovery
A whole cell-based screen of natural product for new anti-TB agents at Novartis identified a compound X displaying potent activity against Mycobacterium tuberculosis (MIC50=0.05-0.1N<M). This compound is active against multidrug resistant clinical isolates, implying a new target. A preliminary study to identify the putative target of this compound was carried out to elucidate its mechanism of action. In a pull-down experiment with immobilized compound X and BCG lysate, ClpC was identified as the potential target. ClpC is an ATPase hexameric protein that catalyze the unfolding, disassembly and disaggregation of specific substrates in bacteria. ClpC subunit interact with the serine protease ClpP to form ATP-dependent proteases. Frequency mutation analysis with compound X did not reveal any mutation of the gene coding for ClpC in M. tuberculosis. However, the basal ATPase activity of ClpC in vitro was found to be enhanced in the presence of compound X. Such uncontrolled activation leads to inhibition of bacterial growth and suggest that ClpC ATPase control several key processes of importance for the multiplication of M. tuberculosis.
mycobacterium, tuberculosis, natural product, ClpC, drug discovery, ATPase
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