Chlamydia trachomatis is most common sexually transmitted bacterial pathogen worldwide. Although chlamydial infections have historically been successfully treated with azithromycin or doxycycline, in recent years the rate of treatment failures has increased, in large part due to the adoption of antibiotic- or cytokine-induced persistent phenotypes. In recent years, menaquinone-7 (MK-7) has emerged as an attractive target for antibiotic development due to its critical role in the electron transport chain as an electron carrier. Chlamydia has recently been shown to produce MK-7 through the newly discovered futalosine pathway, an alternative to the classical pathway found overwhelmingly in most bacteria. This critical role of MK-7 in respiration and its distinct biosynthetic pathway in C. trachomatis presents an exciting opportunity to develop narrow spectrum antibiotics, leaving commensal flora unharmed. We first exposed HeLa exocervical cells infected with C. trachomatis L2(434/Bu) strain to docosahexaenoic acid (DHA), a small molecule discovered by Matsui and coworkers that inhibited the futalosine pathway in H. pylori (Journal of Infection and Chemotherapy 2016, 22, 9, 587–592). In a dose-dependent manner, DHA dramatically reduced the inclusion number and infectious progeny of C. trachomatis within HeLa cells, suggesting that futalosine pathway inhibition may form the basis for antichlamydials. Since the molecular target of DHA is unknown, we have focused our futalosine pathway inhibition studies on the C. trachomatis enzyme CT263 (MqnB), a 5-methyl-thioadenosine nucleosidase (MTAN)-like enzyme responsible for the conversion of 6-amino-6-deoxyfutalosine to hypoxanthine futalosine and adenine. Since CT263 shares structural similarity to the MTANs, a class of nucleosidases from which transition-state based inhibitors have been successfully developed by Schramm and coworkers (J. Am. Chem. Soc. 2015, 137, 45, 14275–14280), we have designed and synthesized small molecule CT263 inhibitor candidates and will describe the progress toward their characterization in vitro and in human cellular models of chlamydial infection.

Taylor Outlaw

Graduate Student, Duke University

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