This is a resubmission of a proposal to characterize the origin of multidrug-resistant clones of E. coli associated with urinary tract infections (UTI). Community-acquired multidrug-resistant UTI is an emerging drug-resistant infectious disease problem worldwide. Our recent studies suggest that drug resistant UTI prevalence in a community can suddenly increase by the introduction of a clonal group of drug-resistant E. coli strains. In a population-based study in California, we found that strains of E. coil belonging to a single clonal group called CgA were responsible for 50% of drug-resistant UTI among women in a college campus. The same clonal group was identified among drug-resistant UTI E. coli isolates from two college campuses in Midwestern United States. We proposed that these strains were spread by contaminated food products. We also showed that drug resistance in these E. coli isolates is mediated by genetic elements called integrons that carry gene cassettes that encode antibiotic resistance. In this project, we wish to demonstrate that drug-resistant uropathogenic E. coli strains acquire their resistance determinants in the food animal reservoir exposed to subtherapeutic doses of antibiotics. We hypothesize that these cassettes are transferred from animal Enterobacteriaceae species to E. coli strains in the animal reservoir. These E. coli strains then cause UTI in women. We will first analyze our large collection of drug-resistant uropathogenic E. coli isolates obtained from population-based studies for integron prevalence, class, and distribution, as well as for cassette type and sequences. We will then compare these cassette sequences to those of well-characterized multidrug-resistant animal E. coli isolates, as well as multidrug-resistant Salmonella typhimurium DT104 isolates. These findings should identify not only the distribution and extent of drug resistance determinants in major pathogenic Enteropacteriaceae species, but if our findings support the foodborne UTI hypothesis, we would be demonstrating that foodborne drug-resistant infectious disease problems in the United States are much greater in scope and disease spectrum than previously believed. This knowledge should lead to the implementation of improved control of drug-resistant infectious diseases.
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