Fluoroquinolones trap gyrase and topoisomerase IV on DNA as ternary complexes in which the DNA is broken. The complexes, called cleaved complexes, block bacterial replication, transcription, and cell growth. At elevated concentrations, fluoroquinolones kill bacteria by two pathways, presumably initiated by release of DNA breaks from the cleaved complexes. Factors that interfere with cleaved complex formation lower susceptibility to fluoroquinolones. Among these factors are changes in drug permeability and efflux, the presence of gyrase-protecting proteins and drug-modifying enzymes, and alteration of target topoisomerases. Selective amplification of resistant mutant subpopulations occurs when drugs inhibit the growth of wild-type bacteria but not that of resistant mutants. This drug-mediated enrichment of resistant mutant subpopulations occurs within a specific drug concentration range (mutant selection window). For most pathogens, fluoroquinolone concentrations during treatment are inside the window determined with cultured cells - emergence of resistance is restricted by drug concentrations above the selection window. When combined with pharmacokinetics, the upper window boundary can be used to compare compounds and dosing regimens for their ability to restrict the selective amplification of resistant mutant subpopulations. Plasmid-encoded factors, which commonly reduce susceptibility only modestly, are likely to contribute significantly to high-level, target-based resistance by acting as early steps in the stepwise accumulation of resistance determinants. Controlling fluoroquinolone resistance requires the reduction of inappropriate antimicrobial use and the development of new derivatives that are: (i) insensitive to existing resistance mutations and (ii) active enough to be safe at concentrations that block the emergence of new mutants.
|Original language||English (US)|
|Title of host publication||Bacterial Resistance to Antibiotics|
|Subtitle of host publication||From Molecules to Man|
|Number of pages||37|
|State||Published - Mar 14 2019|
Bibliographical notePublisher Copyright:
© 2020 John Wiley & Sons Ltd.
- Mutant prevention concentration
- Topoisomerase IV