Activation of multiple antibiotic resistance in uropathogenic Escherichia coli strains by aryloxoalcanoic acid compounds

Clofibric and ethacrynic acids are prototypical pharmacological agents admi nistered in the treatment of hypertrigliceridemia and as a diuretic agent, respectively. They share with 2,4 dichlorophenoxyacetic acid (the widely us ed herbicide known as 2,4-D) a chlorinated phenoxy structural moiety. These aryloxoalcanoic agents (AOAs) are mainly excreted by the renal route as un altered or conjugated active compounds. The relatedness of these agents at the structural level and their potential effect on therapeutically treated or occupationally exposed individuals who are simultaneously undergoing a b acterial urinary tract infection led us to analyze their action on uropatho genic, clinically isolated Escherichia coli strains. We found that exposure to these compounds increases the bacterial resistance to an ample variety of antibiotics in clinical isolates of both uropathogenic and nonpathogenic E. coli strains. We demonstrate that the AOAs induce an alteration of the bacterial outer membrane permeability properties by the repression of the m ajor porin OmpF in a micF-dependent process. Furthermore, we establish that the antibiotic resistance phenotype is primarily due to the induction of t he MarRAB regulatory system by the AOAs, while other regulatory pathways th at also converge into micF modulation (OmpR/EnvZ, SoxRS, and Lrp) remained unaltered. The fact that AOAs give rise to uropathogenic strains with a dim inished susceptibility to antimicrobials highlights the impact of frequentl y underestimated or ignored collateral effects of chemical agents.