Quinolone Antimicrobial Agents, 3rd Edition

Abstract

This chapter introduces the quinolones with a brief consideration of DNA topoisomerases and quinolone target preference. Throughout the chapter attention is given to fluoroquinolone structure. Recently discovered examples include the relaxation of supercoils associated with infection of cultured macrophages by Salmonella enterica serovar Typhimurium and with hydrogen peroxide treatment of Escherichia coli. The bacterial topoisomerases are divided into three groups: type I (topoisomerases I and III), type II (gyrase and topoisomerase IV), and specialized topoisomerases (enzymes that catalyze transposition or integration/excision of bacteriophage DNA from the bacterial chromosome). A function of topoisomerase I is the topological destabilization of transcription-mediated R loops. Another is likely to be control of global supercoiling, since a topA defect that raises supercoiling also suppresses a mukB mutation, a defect that has a global effect on chromosome condensation. Quinolone binding to these mutant gyrase-DNA complexes induces a conformational change that can be detected in the GyrB subunit by limited proteolysis. The location of the quinolone-gyrase-DNA complexes on the bacterial chromosome is likely to influence the potential damage that quinolones can cause. The bacteriostatic effects of the quinolones are now understood at a level sufficient to allow structure-function interpretations. From a clinical perspective, there is a need to identify safe compounds that rapidly kill bacteria, especially resistant mutants. However, further refinement could become an academic exercise if ways are not developed to slow the emergence of fluoroquinolone-resistant pathogens.