Bacterial keratitis is a sight-threatening condition often caused by Gram-negative organisms. A recent study of keratitis caused by multidrug-resistant E. coli highlights the need to better understand how these bacteria adapt to cause disease on the ocular surface. The long-term objective of this proposal is to build a greater understanding of the bacterial factors that contribute to corneal disease, and to target key processes for therapeutic development. The near-term objective is to provide the candidate with additional training in corneal immunobiology and host-pathogen interactions through a one-year mentored training experience, which will serve as a springboard to launch an independent research career developing new treatment strategies for drug-resistant microbial infections of the ocular surface. The candidate has abundant experience in molecular microbiology and microbial genomics, and now seeks additional training in a new but related field before launching an independent research career. As the candidate's mentor describes, the candidate is an outstanding trainee with abundant potential and a broad set of skills and experiences that she now seeks to apply to the to the development of new treatments for infections of the eye that are confounded by antimicrobial resistance. The candidate has an outstanding track record of achievement in research, training and leadership. She has successfully competed for independent research funding, and she is creative, hard working, highly collaborative, and has strong communication skills. In the mentor's own words, Dr. Van Tyne ?is an ideal candidate for a K99/R00 award.? The environment is well suited to the candidate's proposal. The Mass Eye and Ear combines world- class clinical practice and research excellence in a single institution. The Department of Ophthalmology is a high quality research environment with many investigators that are capable of productive collaboration with the candidate, and has a demonstrated track record of providing successful training and career development. The Infectious Disease Institute maintains a clinical strain collection that will be a unique resource leveraged by this project. The Gilmore lab is generously funded and can offer additional support and resources to the candidate's project. The research plan put forth by the candidate consists of three aims.
Aim 1 will investigate E. coli survival in human tears and human serum.
Aim 2 will answer the question: how does mucoidy alter the host- microbe dynamic? Aim 3 will utilize comparative genomics approaches to compare large populations of Gram- negative ocular bacterial pathogens with bacteria from other infection sites, in order to identify genetic features that contribute to tissue tropism.
This research proposal will test the hypothesis that the immune defenses at the ocular surface select for bacteria with traits that enable them to survive and infect this immunologically unique site. In the long term, this project will increase understanding of bacterial factors that contribute to ocular surface disease, and will identify key processes for the development of new therapeutic approaches.
| Kim, Wooseong; Zhu, Wenpeng; Hendricks, Gabriel Lambert et al. (2018) A new class of synthetic retinoid antibiotics effective against bacterial persisters. Nature 556:103-107 |
| Keohane, Colleen E; Steele, Andrew D; Fetzer, Christian et al. (2018) Promysalin Elicits Species-Selective Inhibition of Pseudomonas aeruginosa by Targeting Succinate Dehydrogenase. J Am Chem Soc 140:1774-1782 |
| Dabul, Andrei Nicoli Gebieluca; Avaca-Crusca, Juliana Sposto; Van Tyne, Daria et al. (2018) Resistance in In Vitro Selected Tigecycline-Resistant Methicillin-Resistant Staphylococcus aureus Sequence Type 5 Is Driven by Mutations in mepR and mepA Genes. Microb Drug Resist 24:519-526 |
