Quinolone mode of action--new aspects.
The interactions of quinolones with the complex of DNA gyrase and DNA have been elucidated by the sequencing of additional mutant gyrA and gyrB genes that produce altered quinolone susceptibility. Strong patterns have emerged in Escherichia coli in which amino acids between positions 67 and 106 of the gyrase A subunit (GyrA) and at positions 426 and 447 of the gyrase B subunit (GyrB) have been consistently identified as important for quinolone action. The susceptibility patterns and changes in amino acids 426 and 447 in mutant resistant GyrB proteins suggest direct electrostatic interactions with quinolones at these positions. The small size and the polar nature of the serine at position 83 of the E. coli GyrA protein are particularly important for determining enzyme sensitivity and bacterial susceptibility to quinolones. Norfloxacin and ciprofloxacin bind most stably to a complex of DNA gyrase and DNA rather than to either component alone, and reduction of norfloxacin binding to complexes containing resistant GyrA proteins confirms the biological relevance of this direct measure of quinolone interaction with the gyrase-DNA complex. Although recent crystallographic studies have expanded and refine information about gyrase structure at the atomic level, direct determination of the sites of quinolone binding within the gyrase-DNA complex awaits further studies. Although quinolones have little activity against E. coli topoisomerases I and III, topoisomerase IV, a recently described enzyme thought to be involved in chromosome segregation into daughter cells, has homology with GyrA and GyrB, particularly in regions important for quinolone action, and is inhibited by some quinolones in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
Hooper
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DC
Infectious Disease Unit, Massachusetts General Hospital, Harvard Medical School, Boston.
D042462:4-Quinolones; D000890:Anti-Infective Agents / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions; D004926:Escherichia coli; D013329:Structure-Activity Relationship
D042462:4-Quinolones; D000890:Anti-Infective Agents; D004247:DNA; D004250:DNA Topoisomerases, Type II