Whole genome global insight of antibiotic resistance gene repertoire and virulome of high - risk multidrug-resistant Uropathogenic Escherichiacoli

Abstract

Elucidation of genetic determinants via whole genome sequence (WGS) analyses can help understand the high risk multidrug-resistant (MDR) Uropathogenic Escherichia coli (UPEC) associated with urinary tract infections (UTI) and its evasion strategies from treatment. We investigated the WGS of 30 UPEC strains from UTI samples across the world (2016–2019) and found 25 UPEC strains carrying 2–23 antibiotic resistance genes (ARGs) scattered across 1–3 plasmids per strain. Different ARGs (blaTEM, blaCTXM, blaNDM, blaOXA, blaCMY) encoding extended-spectrum beta-lactamases (TEM, CTXM, CMY) and carbapenemases (NDM, OXA) were found in 24/30, ARGs encoding aminoglycoside modifying enzymes (AAC, APH, AAD) variants in 23/30, trimethoprim ARGs (dfrA17, dfrA12, dfrA5, dfrB4 variants) encoding dihydrofolate reductase in 19/30 and sulfonamide ARGs (sul1, sul2, sul3) encoding dihydropteroate synthase and macrolide ARGs (mph1) encoding macrolide 2’ phosphotransferase in 15/30 UPEC strains. Collectively the ARGs were distributed in different combinations in 40 plasmids across UPEC strains with 20 plasmids displaying co-occurrence of multiple ARGs conferring resistance to beta lactam, aminoglycoside, sulfonamide, trimethoprim and macrolide antibiotics. These resistance plasmids belonged to seven incompatibility groups (IncF, IncI, IncC, IncH, IncN, IncB and Col), with IncFI and IncFII being the predominant resistance plasmids. Additionally, we observed co-occurrence of specific mutation pattern in quinolone resistance determining region (QRDR) viz., DNA gyrase (gyrA: S83L, D87N), and topoisomerase IV (parC: S80I, E84V; parE: I529L) in 18/30 strains. The strains also harbored diverse virulence genes, such as fimH, gad, iss, iha, ireA, iroN, cnf1 and san. Multilocus sequence typing (MLST) reconfirmed ST131(n = 10) as the predominant global high-risk clonal strain causing UTI. In summary, our findings contribute to better understand the plasmid mediated ARGs and its encoded enzymes that may contribute in antibiotic inactivation/modification or alteration in the antibiotic target site in high risk MDR hypervirulent UPEC strains causing UTI. The study reinforces the need to characterize and design appropriate inhibitors to counterattack different enzymes and devise strategies to curtail resistance plasmid.