Quinolone resistance in staphylococci: Activities of new nonfluorinated quinolones against molecular targets in whole cells and clinical isolates

The activity of three new, 8-methoxy-nonfluorinated quinolones (NFQs) again st multiple-drug-resistant staphylococci was investigated. First, using Sta phylococcus aureus strains containing point mutations in the serine 84-80 h ot spots of the target genes (gyrA and grLA), cell growth inhibition potenc ies of the NFQs as a result of DNA gyrase and topoisomerase IV inhibition w ere estimated and compared with those of known fluoroquinolones, The NFQs a nd clinafloxacin showed higher affinities toward both the targets than cipr ofloxacin, trovafloxacin and gatifloxacin, Furthermore, the ratio of the ca lculated affinity parameter for DNA gyrase to that for topoisomerase TV was lower in the case of the NFQs, clinafloxacin, and gatifloxacin than in the case of ciprofloxacin and trovafloxacin. These results suggest that the fo rmer group of quinolones is better able to exploit both the targets, Next, using clinical isolates of methicillin-resistant S. aureus (MRSA; n = 34) a nd coagulase-negative staphylococci (CoNS; n = 24), the NFQs and clinafloxa cin were shown to be more potent (MIC at which 90% of the isolates are inhi bited [MIC90] = 2 mug/ml for MRSA and 0.5 mug/ml for CoNS) than ciprofloxac in, trovafloxacin, and gatifloxacin (MIC90 = 16 to >64 mug/ml for MRSA and 4 to >32 mug/ml for CoNS), Bactericidal kinetics experiments, using two MRS A isolates, showed that exposure to the NFQs at four times the MIC reduced the bacterial counts (measured in CFU per milliliter) by greater than or eq ual to3 log units in 2 to 4 h. Overall, the NFQs and clinafloxacin were les s susceptible than the other quinolones to existing mechanisms of quinolone resistance in staphylococci.