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

MORERO NR; ARGARAÑA CE

San Miguel de Tucumán

Congreso; SAIB; 2009

Although ciprofloxacin (CP) is one of the most effective antibiotics against P. aeruginosa infections, resistance to CP 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 CP 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 CP concentrations. Despite some differences in the resistance nature and frequency, all the analyzed strains showed a high percentage of gyrA mutations at high CP concentration, while nfxB was mainly mutated in the groups selected at 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 CP on the emergence of multidrug resistant strains, both in a wild type and hypermutator background.