Activity of fluoroquinolone antibiotics against Plasmodium falciparum in vitro.
The fluoroquinolone antibiotics are structurally related to nalidixic acid. Their primary antibacterial action appears to be mainly due to inhibition of DNA gyrase (DNA topoisomerase II). We determined the activity of several fluoroquinolones in vitro against two strains of Plasmodium falciparum, FCC1 (chloroquine susceptible) and VNS (chloroquine resistant). [3H]hypoxanthine incorporation by malarial parasites was determined at 48 and 96 h. The molarity at which each agent caused a 50% decrease in the incorporation of [3H]hypoxanthine compared with that of drug-free controls was defined as the 50% inhibitory concentration. The fluoroquinolones evaluated were amifloxacin, ciprofloxacin, enoxacin, norfloxacin, ofloxacin, and pefloxacin. Other DNA gyrase inhibitors tested were nalidixic acid, oxolinic acid, novobiocin, and coumermycin A1. Among the fluoroquinolones, ciprofloxacin had the lowest 50% inhibitory concentrations at 48 h against both chloroquine-susceptible and -resistant strains of P. falciparum, (0.26 +/- 0.08) x 10(-4) and (0.38 +/- 0.15) x 10(-4) M, respectively (mean +/- standard deviation). Enoxacin had the lowest 50% inhibitory concentrations against FCC1 and VNS at 96 h, 0.23 x 10(-5) and (0.06 +/- 0.04) x 10(-5) M, respectively. With the VNS strain, fractional inhibitory concentration indexes for the combination of ciprofloxacin and tetracycline were calculated at 48 and 96 h to be 0.93 and 0.79, respectively, indicating modest additive effects. The combination of novobiocin with ciprofloxacin showed indifference in the same system. The antimalarial effects of some fluoroquinolones occur at achievable serum concentrations. Whether inhibition of DNA gyrase contributes to the antimalarial activity of the fluoroquinolones is unknown at present.
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Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
Sartorelli
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Patton
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D049933:Aminocoumarins; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D002939:Ciprofloxacin / Q000031:analogs & derivatives / Q000494:pharmacology; D003374:Coumarins / Q000494:pharmacology; D004347:Drug Interactions; D004351:Drug Resistance; D015365:Enoxacin / Q000494:pharmacology; D024841:Fluoroquinolones; D009268:Nalidixic Acid / Q000494:pharmacology; D009643:Norfloxacin / Q000494:pharmacology; D009675:Novobiocin / Q000494:pharmacology; D015242:Ofloxacin / Q000494:pharmacology; D010093:Oxolinic Acid / Q000494:pharmacology; D015366:Pefloxacin / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects*; D013752:Tetracycline / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
D049933:Aminocoumarins; D000890:Anti-Infective Agents; D003374:Coumarins; D024841:Fluoroquinolones; D059005:Topoisomerase II Inhibitors; D009675:Novobiocin; D015366:Pefloxacin; D015365:Enoxacin; D009268:Nalidixic Acid; D002939:Ciprofloxacin; C040691:amifloxacin; D002738:Chloroquine; D015242:Ofloxacin; D013752:Tetracycline; D010093:Oxolinic Acid; D009643:Norfloxacin; C004628:coumermycin