Development of Pantothenate Analogs That Can Treat Combat-Related Infections
Final rept. 1 Jan 2011-31 Dec 2013
TULANE UNIV NEW ORLEANS LA SCHOOL OF MEDICINE
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Increasing reports of antibiotic resistance involving S. aureus and K. pneumoniae and the resulting high mortality rates in the battlefields have emphasized a critical need for the development of antimicrobial compounds with novel modes of action. Fatty acids are known to serve many critical roles in the cell, including energy storage, integrity and dynamics of biological membranes, cellular metabolism, and cellular signaling, and interference with fatty acid metabolism has been proved to be an effective strategy for inhibition of bacterial growth. N-substituted pantothenate analogs have been developed and shown to inhibit the growth of S. aureus and E. coli and probably also K. pneumoniae but have not been tested in preclinical and clinical set-ups, primarily because of their possible interference with human cells. We propose to elucidate differences in the architecture of the compound-pantothenate kinase-binding site between humans and bacteria using x-ray crystallographic techniques and exploit these differences to develop new compounds specific for the drug-resistant bacterial strains. These new compounds will have the potential to control infections caused by S. aureus and K. pneumoniae, thus improving the survival rate of military personnel wounded in combat. Candidate compounds identified in this study should first be tested in animal models to determine their response to the treatment and subsequently in clinical trials to test the efficacy of this novel approach in humans. Our efficient procedure of the iteration of the computer prediction and experimental verifications with the sufficient feedback will enable us to identify novel drug candidates, which are characterized by fewer side-effects, less likelihood of drug resistance, and will be available to public at costs substantially below industry average.
- Medicine and Medical Research