A High-Throughput Screen against Pantothenate Synthetase (PanC) Identifies 3-Biphenyl-4-Cyanopyrrole-2-Carboxylic Acids as a New Class of Inhibitor with Activity against <i>Mycobacterium tuberculosis</i>

<div><p>The enzyme pantothenate synthetase, PanC, is an attractive drug target in <i>Mycobacterium tuberculosis</i>. It is essential for the <i>in vitro</i> growth of <i>M. tuberculosis</i> and for survival of the bacteria in the mouse model of infection. PanC is absent from mammals. We developed an enzyme-based assay to identify inhibitors of PanC, optimized it for high-throughput screening, and tested a large and diverse library of compounds for activity. Two compounds belonging to the same chemical class of 3-biphenyl-4- cyanopyrrole-2-carboxylic acids had activity against the purified recombinant protein, and also inhibited growth of live <i>M. tuberculosis</i> in manner consistent with PanC inhibition. Thus we have identified a new class of PanC inhibitors with whole cell activity that can be further developed.</p>