The roles of fosfomycin resistant subpopulations of Escherichia coli in urinary tract infection.

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PROJECT SUMMARY/ABSTRACT Urinary tract infections (UTIs) are one of the most common bacterial infections worldwide and the bacteria that cause them are becoming increasing resistant to frontline antibiotics. As a result, last resort antibiotics, like fosfomycin, are beginning to be more frequently prescribed. Uropathogenic Escherichia coli (UPEC), which is the primary cause of UTIs, can become resistant to fosfomycin, through mutations that impair the function or production of the UhpT transporter, which imports fosfomycin into the bacterial cell. The current paradigm is that such mutations come at a fitness tradeoff because impairment of UhpT limits the import of the glycolysis intermediate glucose-6-phosphate. However, my preliminary data indicate that mutations that lead to increased resistance to fosfomycin by abrogating uhpT expression, do not impede colonization of the host urinary tract. In fact, loss of fosfomycin import demonstrates increased persistence during long-term infection. Additionally, I have shown that 77% of screened UPEC clinical isolates harbor fosfomycin resistant subpopulations. This raises the alarming hypothesis that fosfomycin resistant subpopulations arise during UTI, possibly in response to a host-imposed stress and may provide additional fitness advantages for the pathogen. I will test this hypothesis through two specific aims which will: determine the contribution of fosfomycin resistant subpopulations to UPEC pathogenesis (Aim 1) and elucidate the basis of prolonged bacteriuria during UPEC pathogenesis following loss of uhpBA (Aim 2). Together my studies will provide insights that will ultimately help us curb the onset and propagation of resistance to one of the last- resort antibiotic agents, by thoroughly elucidating novel mechanisms that lead to fosfomycin resistance during infection and gauging their fitness advantages and disadvantages in comparison to their parental strains. Through the execution of these aims, I will cultivate valuable skills in genomic analysis, advanced microscopy techniques, eukaryotic cell culture, and comprehensive analysis of host-pathogen interactions.