Honors College Thesis
 

Mechanism of action of ST-669 in Chlamydia spp.

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  • Our laboratory group is studying the molecular target of a novel, broad-spectrum antiviral compound known as ST-669. This compound has activity against a variety of different viruses and also obligate intracellular bacteria in the genera Coxiella and Chlamydia. The goal of this thesis project was to help elucidate the mechanism of action of ST-669 by evaluating the hypothesis that ST-669 acts as an inhibitor of host sphingomyelin production. In this study, we examine the salvage pathway of sphingomyelin synthesis and compared and contrasted the effects of ST-669 and the effects of myriocin, a potent sphingomyelin inhibitor, on this pathway. ST-669 and myriocin were used to examine the inclusion structure of C. caviae: when treated with ST-669 or myriocin, inclusions with single-lobes were observed, which is atypical of C. caviae growing in cell culture. It is believed that these compounds are disrupting inclusion membrane integrity resulting in fusion of vacuoles and formation of single-lobed inclusions. Treatment of infected cells with sphingosine, a sphingomyelin precursor, complemented the effects of myriocin, returning the inclusions to their typical, multi-lobed phenotype. However, treatment of infected cells with sphingosine did not alter the effects of ST-669 on C. caviae inclusion morphology. These results support a conclusion that the molecular target of ST-669 is different from that of myriocin. ST-669 maybe acting on a different host protein that influences chlamydial inclusion formation. These results may lead to future proteomic studies that may help elucidate ST-669’s mechanism of action or may offer a greater understanding of inclusion membrane formation in C. caviae. Key Words: Chlamydia, Inclusion, ST-669, Sphingomyelin, Antimicrobial
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  • URISC, URSA-Engage, Ken & Paula Krane Experiential Learning Scholarship
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