Plasmid-mediatedqnrgenes provide only a modest decrease in quinolone susceptibility but facilitate the selection of higher-level resistance. InEscherichia colistrain J53 withoutqnr, ciprofloxacin resistance often involves mutations in the GyrA subunit of DNA gyrase. Mutations ingyrAwere absent, however, when 43 mutants with decreased ciprofloxacin susceptibility were selected from J53(pMG252) withqnrA1. Instead, in 13 mutants, individual and whole-genome sequencing identified mutations inmarRandsoxRassociated with increased expression ofmarAandsoxSand, through them, increased expression of the AcrAB pump, which effluxes quinolones. Nine mutants had increased expression of the MdtE efflux pump, and six demonstrated increased expression of theydhEpump gene. Many efflux mutants also had increased resistance to novobiocin, another pump substrate, but other mutants were novobiocin hypersusceptible. Mutations inrfaDandrfaEin the pathway for inner core lipopolysaccharide (LPS) biosynthesis were identified in five such strains. Many of the pump and LPS mutants had decreased expression of OmpF, the major porin channel for ciprofloxacin entry. Three mutants had increased expression ofqnrAthat persisted when pMG252 from these strains was outcrossed.gyrAmutations were also rare when mutants with decreased ciprofloxacin susceptibility were selected fromE. coliJ53 withaac(6′)-Ib-crorqepA. We suggest that multiple genes conferring low-level resistance contribute to enhanced ciprofloxacin resistance selected from anE. colistrain carryingqnrA1,aac(6′)-Ib-cr, orqepAbecause these determinants decrease the effective ciprofloxacin concentration and allow more common but lower-resistance mutations than those ingyrAto predominate.
Adaptive mutations produce resistance to ciprofloxacin.
