title: Intracellular targets of moxifloxacin: a comparison with other fluoroquinolones.
abstract: The in vitro activity of the novel 8-methoxyquinolone, moxifloxacin, against Streptococcus pneumoniae was evaluated, and the intracellular targets of this agent were studied. Analysis of mutant strains selected with moxifloxacin demonstrated that first-step mutants bore amino acid substitutions at position 81 in the GyrA subunit of DNA gyrase. This suggests that, unlike older fluoroquinolone agents such as ciprofloxacin and levofloxacin, but similar to other C-8 substituted quinolones like sparfloxacin and gatifloxacin, moxifloxacin targets the GyrA subunit of DNA gyrase as an initial lethal event. Such a mechanism results in high activity against increasingly common S. pneumoniae strains bearing substitutions in DNA topoisomerase IV. Moxifloxacin was active with an MIC of </= 0.25 mg/L against S. pneumoniae clinical isolates, and against mutants, selected in the laboratory with ciprofloxacin or levofloxacin, that bore a Ser-79-->Phe/Tyr substitution in ParC. The moxifloxacin MIC for strains with mutations in the structural genes for both DNA gyrase subunit GyrA and DNA topoisomerase IV subunit ParC did not exceed 2 mg/L, a level within clinically achievable serum concentrations for this agent. We also found that moxifloxacin is a poor substrate for active efflux in S. pneumoniae. Therefore, the high activity of moxifloxacin against S. pneumoniae appears to be a result of both enhanced activity against DNA gyrase and topoisomerase IV, and reduced efflux from the bacterial cell.
authors.affiliation: Departments of Pathology and Medicine, Northwestern University Medical School, Divisions of Microbiology and Infectious Diseases, Northwestern Memorial Hospital, Chicago, IL 60611, USA.
authors.forename: E
authors.initials: E
authors.lastname: Pestova
authors.forename: J J
authors.initials: JJ
authors.lastname: Millichap
authors.forename: G A
authors.initials: GA
authors.lastname: Noskin
authors.forename: L R
authors.initials: LR
authors.lastname: Peterson
mesh_terms: D000890:Anti-Infective Agents / Q000378:metabolism / Q000494:pharmacology*; D001372:Aza Compounds; D004264:DNA Topoisomerases, Type I / Q000187:drug effects / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000187:drug effects / Q000378:metabolism; D004352:Drug Resistance, Microbial; D024841:Fluoroquinolones; D006801:Humans; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009154:Mutation; D011008:Pneumococcal Infections / Q000382:microbiology*; D016133:Polymerase Chain Reaction; D011804:Quinolines; D012110:Reserpine / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development
chemical_list: D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D012110:Reserpine; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; C061363:sparfloxacin; D000077266:Moxifloxacin