title: Gatifloxacin activity against quinolone-resistant gyrase: allele-specific enhancement of bacteriostatic and bactericidal activities by the C-8-methoxy group.
abstract: Antibacterial activities of gatifloxacin (AM1155), a new C-8-methoxy fluoroquinolone, and two structurally related compounds, AM1121 and ciprofloxacin, were studied with an isogenic set of ten quinolone-resistant, gyrA (gyrase) mutants of Escherichia coli. To compare the effect of each mutation on resistance, the mutant responses were normalized to those of wild-type cells. Alleles exhibiting the most resistance to growth inhibition mapped in alpha-helix 4, which is thought to lie on a GyrA dimer surface that interacts with DNA. The C-8-methoxy group lowered the resistance due to these mutations more than it lowered resistance arising from several gyrA alleles located outside alpha-helix 4. These data are consistent with alpha-helix 4 being a distinct portion of the quinolone-binding site of GyrA. A helix change to proline behaved more like nonhelix alleles, indicating that helix perturbation differs from the other changes at helix residues. Addition of a parC (topoisomerase IV) resistance allele revealed that the C-8-methoxy group also facilitated attack of topoisomerase IV. When lethal effects were measured at a constant multiple of the minimum inhibitory concentration for each fluoroquinolone to normalize for differences in bacteriostatic action, gatifloxacin was more potent than the C-8-H compounds, both in the presence and absence of protein synthesis (an exception was observed when alanine was substituted for aspartic acid at position 82). Collectively, these data show that the C-8-methoxy group contributes to the enhanced activity of gatifloxacin against resistant gyrase and wild-type topoisomerase IV.
authors.affiliation: Public Health Research Institute, New York, New York 10016, USA.
authors.forename: T
authors.initials: T
authors.lastname: Lu
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.forename: K
authors.initials: K
authors.lastname: Drlica
mesh_terms: D000483:Alleles; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000235:genetics*; D027081:DNA Gyrase; D027101:DNA Topoisomerase IV; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D004352:Drug Resistance, Microbial; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D024841:Fluoroquinolones; D000077734:Gatifloxacin; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D000890:Anti-Infective Agents; D004269:DNA, Bacterial; D024841:Fluoroquinolones; D059005:Topoisomerase II Inhibitors; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase; D004250:DNA Topoisomerases, Type II; D000077734:Gatifloxacin