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PubMed · 7791428

Quinolones.

B Suh·B Lorber
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Abstract

Fluoroquinolones represent a major advance in antimicrobial chemotherapy. Currently, there are five fluoroquinolones approved by the FDA, and many more quinolones are expected to become available in years to come. Although their clinical utility is constantly expanding, they have been best studied in complicated urinary tract infections, chronic osteomyelitis caused by gram-negative bacilli, bacterial gastrointestinal infections such as traveler's diarrhea and typhoid fever, and uncomplicated gonococcal infections and in the prophylaxis of bacterial infections in patients with neutropenia. These agents have the convenience of oral administration, favorable pharmacokinetic properties, and low toxicity profiles but should be used advisedly because indiscriminate use may result in the early emergence of resistance.

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4-QuinolonesAnti-Infective AgentsBacterial InfectionsDrug InteractionsHumansMicrobial Sensitivity TestsJournal ArticleReview

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BibTeXRIS

B Suh, B Lorber. 1995. Quinolones.. https://doi.org/10.1016/s0025-7125(16)30044-x

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Previous studies have shown that topoisomerase IV and DNA gyrase interact with quinolones and coumarins in different ways. The MICs of coumarins (novobiocin and coumermycin) for MT5, a Staphylococcus aureus nov mutant, are higher than those for wild-type strains. Sequencing the gyrB gene encoding one subunit of the DNA gyrase revealed the presence of a double mutation likely to be responsible for this resistance: at codon 102 (Ile to Ser) and at codon 144 (Arg to Ile). For single-step flqA mutant MT5224c9, previously selected on ciprofloxacin, the fluoroquinolone MIC was higher and the coumarin MIC was lower than those for its parent, MT5. Sequencing the grlB and grlA genes of topoisomerase IV of MT5224c9 showed a single Asn-470-to-Asp mutation in GrlB. Genetic outcrosses by transformation with chromosomal DNA and introduction of plasmids carrying either the wild-type or the mutated grlB gene indicated that this mutation causes both increased MICs of fluoroquinolones and decreased MICs of coumarins and that the mutant grlB allele is codominant for both phenotypes with multicopy alleles. Integration of these plasmids into the chromosome confirmed the codominance of fluoroquinolone resistance, but grlB+ appeared dominant over grlB (Asp-470) for coumarin resistance. Finally, the gyrA (Leu-84) mutation previously described as silent for fluoroquinolone resistance increased the MIC of nalidixic acid, a nonfluorinated quinolone. Combining the grlA (Phe-80) and grlB (Asp-470) mutations with this gyrA mutation also had differing effects. The findings indicate that alterations in topoisomerases may have pleiotropic effects on different classes of inhibitors as well as on inhibitors within the same class. A full understanding of drug action and resistance at the molecular level must take into account both inhibitor structure-activity relationships and the effects of different classes of topoisomerase mutants.

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