Novel Strategy for Endophthalmitis Drug Targets

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DESCRIPTION (provided by applicant): Endophthalmitis (inflammation inside the eye) is a serious threat to vision following ocular surgical procedures such as cataract surgery. Millions of cataract surgeries are performed per year in the United States and the number of these surgeries is expected to increase with an aging population, with an expected accompanying rise in the number of endophthalmitis cases. Treatment of endophthalmitis can be challenging given the dramatic increase in drug resistance in the etiologic agents of endophthalmitis. Enterococcus faecalis causes an unusually destructive and drug-resistant form of endophthalmitis that often leads to blindness. The goal of this research is to identify new drug targets for intraocular E. faecalis using innovative in vitro endophthalmitis models. Because the inside of the eye is normally sterile, invading microbes such as E. faecalis encounter a novel environment during endophthalmitis-that environment is the fluid inside the eye, the vitreous humor. Because vitreous humor is a novel environment for E. faecalis, we hypothesize that E. faecalis modulates its gene expression in response to vitreous humor in order to survive and proliferate there. E. faecalis genes expressed in vitreous humor likely influence endophthalmitis pathogenesis and patient vision outcomes and products of these genes are potential drug targets. The specific aims are to: 1. Identify E. faecalis genes expressed in an in vitro endophthalmitis model. Global gene expression profiling will be used to identify E. faecalis genes differentially regulated in response to vitreous humor, in particular those genes that allow E. faecalis to survive and grow inside the vitreous. Genetic techniques will lay a foundation for future animal model studies to evaluate the contribution of these genes to experimental endophthalmitis. 2. Design a tractable nutritional model of the eye. We will use rigorous quantitative analysis to define key contributors to the permissive growth environment of vitreous humor. These data will be used to develop a defined E. faecalis growth medium mimicking vitreous humor composition such that specific components can be manipulated, removed, or targeted with drugs to address their role in E. faecalis metabolism and virulence. PUBLIC HEALTH RELEVANCE: Endophthalmitis is an important public health concern because of the severe visual outcomes of this disease-near or complete blindness. Resistance of microbes causing endophthalmitis to last-line antibiotics is of extreme concern. This research will identify new drug targets for the antibiotic-resistant endophthalmitis microbe E. faecalis that can be used to thwart the devastating visual outcomes of endophthalmitis.