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"Keeping the ‘Scourge of Armies’ in a state of Anonymity: Drug Discovery Developments against Rickettsia spp"

Alexander Lemenze
Infection, Immunity and Inflammation Program
B.S. 2013, Rochester Institute of Technology, Rochester NY

Thesis Advisors, Nancy Connell, Ph.D.
Professor, Department of Medicine
Robert J. Donnelly, Ph.D.
Professor, Department of Pathology and Laboratory Medicine

Friday, January 12, 2018
11:00 A.M., MSB B610


Rickettsia is a genus of Gram-negative, obligate intracellular pathogens that have for centuries caused large scale morbidity and mortality. After the advent of the antibiotic era it has been seen as a pathogen of lesser note and subsequently has been primarily ignored for drug discovery. In more recent years, the resurgence of Rickettsial diseases as a major cause of Fevers of Unknown Origin (FUO), bioterrorism concerns, and increasing evidence of drug resistance on the horizon are driving a need to identify novel treatments. Drug discovery against Rickettsia spp is currently minimal to non-existent due to difficulties arising from its obligate intracellular nature. Utilizing the pRAM18dRGA plasmid bearing an uvGFP gene, we developed a novel drug screening assay for identifying anti-Rickettsial compounds that drastically reduced cost and time constraints. Furthermore, to improve the statistical likelihood of identifying efficacious compounds, we applied Bayesian Machine Learning algorithms for screening of additional compounds in silico. This dual-prong methodology identified two anti-Rickettsial compounds, Duartin and JSF-3204. Through mechanistic studies, we have characterized these two novel compounds as highly specific, efficacious, and non-cytotoxic compounds that act in a translational inhibitory mechanism. In the end, our methodology can be implemented for further drug discovery efforts against Rickettsia spp, and our two compounds; Duartin and JSF-3204, can undergo further validation as potential clinical treatments for Rickettsioses.

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