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Terfendine as a new S. aureus antibiotic

The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species) cause the majority of U.S. healthcare-associated infections and can “escape” the therapeutic activity of current antibiotics, making the pursuit of new antimicrobial agents effective against these bacteria a high priority. In a high-throughput screen of a library of FDA-approved drugs against the ESKAPE pathogens, 38 compounds were newly reported to have bactericidal activity as indicated by the release of adenylate kinase (AK) from killed bacterial cells. Assay results revealed that the antihistamine, terfenadine, displays impressive antimicrobial activity toward S. aureus and other Gram-positive bacterial pathogens tested.

The first objective of this project was to determine the antimicrobial mechanism of action of terfenadine against S. aureus. Our hypothesis was that terfenadine is a type II topoisomerase inhibitor based on its structural similarity to that of another novel topoisomerase inhibitor. Gel-based in vitro assays revealed that terfenadine is able to significantly inhibit the functions of the activities of two essential bacterial type II topoisomerases, DNA gyrase and topoisomerase IV.

The second objective was to determine the structure-activity relationship (SAR) of terfenadine and its analogs in order to optimize its antibacterial activity and develop a more effective antibiotic against S. aureus. In order to study the SAR of terfenadine and its 86 analogs, we compared each compound’s antimicrobial activity and in vitro enzyme inhibition. Antimicrobial testing against S. aureus revealed that changes in the functional group on the para-position on one of the phenyl rings on the terfenadine molecule were able to significantly alter the antimicrobial ability of the compounds.

The results show that the polarity of this group is thus far the biggest factor determining anti- S. aureus activity. This indicates that this group plays an important role in the interaction of the molecule and its target. Moreover, the SAR corresponds directly with the ability of the compounds to inhibit both enzymes in vitro, further supporting our hypothesis on the mechanism of action. These are promising findings since there is a need for new antibiotics effective against S. aureus and terfenadine may represent a new structural class of antimicrobial agents to fulfill this need.

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