Molecular mechanisms of ciprofloxacin resistance in hypermutator strains of P. aeruginosa

MORERO NR

San Miguel de Tucumán

Congreso; XLV Reunión Anual de SAIB; 2009

Although ciprofloxacin is one of the most effective antibiotics against P. aeruginosa infections, resistance to ciprofloxacin emerge quickly in the clinical setting, and is often acompaigned with cross-resistance to other antibiotics. Two major resistance pathways were described: the disruption of drug-target interaction (by mutations in GyrA and ParC subunits of the target topoisomerases), and the expression of multidrug efflux pumps (by mutations in the transcriptional represor NfxB). In this work we analyze the molecular nature of ciprofloxacin resistance for the PAO1 wild type strain and the hypermutators mutS and mutT, defective in the mismatch repair and 8-oxoguanine repair systems respectively. To this purpuse, we sequenced gyrA, parC and nfxB genes for groups of resistant cells selected at different ciprofloxacin concentrations. We report the main resistance pathway and mutational spectrum for each strain, and show that gyrA is predominantly mutated in cells selected at high ciprofloxacin concentrations, while nfxB mutations are dominant al low drug concentration. These nfxB mutants showed cross-resistance to other antibiotics such as erythromycin and trimethoprim. In this context, we discuss the influence of the exposure to low and high doses of ciprofloxacin on the emergence of multidrug resistant strains, both in a wild type and hypermutator background.