Limiting the impact of infectious diseases is one of the main challenges that scientists face. Several approaches can be used to control the spread of contagion and manage the potential consequences of a disease. Heterocyclic compounds have shown promising activity to maintain and improve our health as it relates to infectious diseases. Chlamydia trachomatis (CT), an obligate intracellular bacterium, is the most common bacterial sexually transmitted disease (STD) around the globe. Untreated CT infections may result in pelvic inflammatory disease, ectopic pregnancy, chronic pelvic pain, or trachoma (a form of blindness). Unfortunately, the standard treatments (azithromycin or doxycycline) can have failure rates ranging from 7-15%. Moreover, treatments based on broad spectrum antibiotics can lead to the spread of resistance in S. pneumoniae, S. aureus, E. coli, N. gonorrhoeae, and other species within the microflora. In this talk, I will describe the efforts we have made to develop CT-specific therapeutics. The growth of bacteria such as Chlamydia is tightly regulated by cylindrical proteases, a degradation machinery that regulates protein turnover. We have synthesized pyridine-based compounds that can target cylindrical proteases and display promising activity against CT. We investigated the selectivity of the molecules and their toxicity towards human cells. In addition, we developed a 3D stratified epithelium cell model to mimic the genital tract to study our most active molecules. Further, we assessed the mechanism of action of the compounds and established structure-activity relationships. We performed various structural studies including X-ray crystallography, small angle X-ray scattering, Hydrogen-deuterium exchange experiments, and computational modeling to identify the structure of our target. Our results indicate that pyridine-based molecules are a promising scaffold to develop drugs that are selective for CT. In addition, we have solved the structure of a CT cylindrical protease subunit, which will be key to developing molecules that are selective for this promising target.

Organic and medicinal chemistry meeting biophysics: Solving microbiological problems

ACS Fall 2021

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