Development of Pantothenate Analogs That Can Treat Combat-Related Infections

We have solved the structures of bacterial PanKs from S. aureus, K pneumonia and E. coli in complex with substrate anaogs (N5-Pan and N7-Pan) as well as the structure of human PanK3 in complex with N7-Pan. With the finding that the Pan analog binding site of SaPanK is different from human PanK, we synthesized two new compounds that fit to the Pan analog binding site of SaPanK. Similarly, we are currently synthesizing a drug-like chemical series against KpPanK (or EcPanK) by comparing the N7-Pan binding pockets of KpPanK (or EcPanK) and human PanK3. Afterward, we will optimize the conditions of bacterial colony and cytotoxicity MTT assays for newly synthesized compounds. These studies will result in three sets of new compounds that inhibit the activities of PanKs from three different bacteria. Predictably, each compound set will specifically hamper the growth of respective bacteria, but has minimal effect on human cells. These new compounds will be the basis for further testing in animal models and clinical trials to develop a novel class of narrow-spectrum antibiotics active against the multidrug resistant strains of S. aureus, K. pneumoniae, and E. coli frequently found in battlefield wounds sustained in Iraq and Afghanistan.
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