Antagonism between bactericidal activities of 4-quinolones and coumarins gives insight into 4-quinolone killing mechanisms.
At concentrations exceeding their MICs, novobiocin and coumermycin antagonised the bactericidal activities of nalidixic acid, ciprofloxacin, ofloxacin and norfloxacin against Escherichia coli KL16. The sensitivities to killing by ciprofloxacin of four mutant derivatives of KL16 carrying gyrA, nalB, nal24 or nal31 alleles were also antagonised by novobiocin. The activities of drug combinations were tested in nutrient broth, which allowed expression of 4-quinolone killing mechanisms A, B and C. They were also tested in nutrient broth plus rifampicin to inhibit mechanisms A and C of the 4-quinolones, and in phosphate-buffered saline, which inhibited mechanism A. Results showed that novobiocin antagonised mechanism C, but not B, of both ciprofloxacin and ofloxacin, but did not antagonise mechanism C of norfloxacin. A review of these and other data indicates that mechanism B may result from the activities of SOS error-prone DNA repair on an irreversibly-bound drug-gyrase-DNA complex, and that mechanism C is mediated via drug interaction with the B subunit of DNA gyrase.
Howard
B M
BM
Department of Pharmaceutics, School of Pharmacy, University of London, Brunswick Square, Great Britain.
Pinney
R J
RJ
Smith
J T
JT
D049933:Aminocoumarins; D000890:Anti-Infective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003374:Coumarins / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D005798:Genes, Bacterial / Q000235:genetics; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009268:Nalidixic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009643:Norfloxacin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009675:Novobiocin / Q000494:pharmacology*; D015242:Ofloxacin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology
D049933:Aminocoumarins; D000890:Anti-Infective Agents; D003374:Coumarins; D009675:Novobiocin; D009268:Nalidixic Acid; D002939:Ciprofloxacin; D015242:Ofloxacin; D004250:DNA Topoisomerases, Type II; D009643:Norfloxacin; C004628:coumermycin; D012293:Rifampin