We have examined the antipneumococcal mechanisms of a series of novel fluoroquinolones that are identical to ciprofloxacin except for the addition of a benzenesulfonylamido group to the C-7 piperazinyl ring. A number of these derivatives displayed enhanced activity against Streptococcus pneumoniae strain 7785, including compound NSFQ-105, bearing a 4-(4-aminophenylsulfonyl)-1-piperazinyl group at C-7, which exhibited an MIC of 0.06 to 0.125 g/ml compared with a ciprofloxacin MIC of 1 g/ml. Several complementary approaches established that unlike the case for ciprofloxacin (which targets topoisomerase IV), the increased potency of NSFQ-105 was associated with a target preference for gyrase: (i) parC mutants of strain 7785 that were resistant to ciprofloxacin remained susceptible to NSFQ-105, whereas by contrast, mutants bearing a quinolone resistance mutation in gyrA were four-to eightfold more resistant to NSFQ-105 (MIC of 0.5 g/ml) but susceptible to ciprofloxacin; (ii) NSFQ-105 selected first-step gyrA mutants (MICs of 0.5 g/ml) encoding Ser-81-to-Phe or -Tyr mutations, whereas ciprofloxacin selects parC mutants; and (iii) NSFQ-105 was at least eightfold more effective than ciprofloxacin at inhibiting DNA supercoiling by S. pneumoniae gyrase in vitro but was fourfold less active against topoisomerase IV. These data show unequivocally that the C-7 substituent determines not only the potency but also the target preference of fluoroquinolones. The importance of the C-7 substituent in drug-enzyme contacts demonstrated here supports one key postulate of the Shen model of quinolone action.The renewed interest in antibacterial fluoroquinolones derives from the recent development of agents active against gram-positive pathogens, particularly Streptococcus pneumoniae, the main cause of community-acquired pneumonia (4,7,29). Several new fluoroquinolones, e.g., clinafloxacin, gatifloxacin, gemifloxacin, and moxifloxacin, which are more potent in vitro than ciprofloxacin or levofloxacin, are at various stages of clinical development. With the likely increase in clinical use of antipneumococcal fluoroquinolones, attention has concentrated on their mechanisms of action and resistance in S. pneumoniae.
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