Our long-term goal is to advance the understanding, at the molecular level, of the pathogenicity and epidemiology of uropathogenic Escherichia coli strains to better target treatment and prophylaxis of urinary tract infections (UTIs), reduce antibiotic resistance, and provide information on possible targets for vaccines and antibiotics. The most common cause of fluoroquinolone and multi-drug resistant UTIs are two E. coli strains that comprise clonal groups ST131-H30 and ST1193. Those pandemic multi-drug resistant strains (PMDR) have emerged 1-2 decades ago, are globally spread and, combined, are responsible for 60- 80% of the antibiotic-resistant UTIs. At the same time, PMDR appears to be able persisting for many months, possibly years in the gut and urinary bladder of healthy women, without them having symptoms of UTI or taking antibiotics. The objective of the proposed work is to investigate in detail the frequency, patterns and clinical risks of asymptomatic gut and bladder carriage of PMDR, identify possible means of the carriers de-colonization and compare on a genome-wide scale the PMDR isolates from women without and with UTI. Our preliminary data support that we can investigate sizeable samples of fecal and urine samples, establish the clonal identity of fresh isolates, and determine genome-wide the pathogenicity-adaptive genetic changes. We will determine how mutational changes (single nucleotide polymorphisms, small insertions/deletions, etc.) and horizontal gene transfer contribute to the urovirulence of PMDR. For this, we will employ a population genomics- based analysis to trace the mutations and gene transfer, followed by assessment of the functional significance of the representative positively selected loci in PMDR. practical terms, accomplishment of the proposed studies will advance at the molecular level our understanding of the ecology, pathogenicity, and epidemiology of antibiotic-resistant uropathogenic E. coli and will provide information on possible targets for vaccines, antibiotics, or other therapeutics.