Howard, Bernadette Maria Anne; (1991) Studies on the bactericidal activities of the 4-quinolones. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The 4-quinolones act primarily on the A subunit of DNA gyrase coded by the gyrA gene. The nalA mutation in gyrA was found to abolish mechanism B which is the first evidence that mechanism B may reside within gyrase. The coumarins novobiocin and coumermycin inhibit the B subunit of DNA gyrase. The sensitivities of the Escherichia coli KL16 nalR mutants to both coumarins were investigated. New novobiocin-resistant (novR) and coumermycin resistant (couR) mutants of E.coli KL16 and Staphylococci warneri were isolated and their sensitivities to ciprofloxacin, novobiocin and coumermycin determined. Both species showed incomplete cross-resistance. Other workers have found that the 4-quinolone antibacterials do not seem to interact with the coumarin antibacterials when minimum inhibitory concentration tests were used to judge interactions. However, when bactericidal interactions between the 4- quinolones and novobiocin or coumermycin were studied in this thesis with E.coli KL16 and Staphylococci significant antagonism of the 4-quinolones by the coumarins was found in all combinations tested. These results agreed with in vivo findings, which hence disagreed with the in vitro results of other workers. SOS DNA repair did not repair damage caused by nalidixic acid, while recombination repair did repair damage caused by the drug. Ciprofloxacin- ofloxacin- and norfloxacin-induced damage, however, showed some differences as regards these DNA repair systems. Nalidixic acid possesses only one mechanism of bactericidal activity, termed A, ciprofloxacin and ofloxacin possess mechanisms A, B and C, while norfloxacin possesses mechanisms A and C. Mechanism B, which does not require protein synthesis or RNA synthesis nor bacteria capable of dividing, was found to operate when drug concentrations reached the co-operative binding concentrations with supercoiled DNA. The effect of the 4-quinolones and coumarin antibacterials on DNA supercoiling was investigated by alkaline or in situ lysis. In-situ lysis was found to be more appropiate than alkaline lysis for such investigations. 4-quinolones are known to exhibit post antibiotic effects (PAE's). E.coli KL16, Staph, aureus, Klebsiella pneumoniae and Streptococcus pyogenes were investigated for PAE's with ciprofloxacin, ofloxacin and a new cephalosporin, cefdinir. PAE's were found with all three drugs in Staph, aureus and Strep, pyogenes. However in E.coli PAE's were only found with ciprofloxacin or ofloxacin and were generally absent with Klebsiella pneumoniae.

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