title: Antistaphylococcal activities of the new fluoroquinolone JNJ-Q2.
abstract: The new broad-spectrum fluoroquinolone JNJ-Q2 displays in vitro activity against Gram-negative and Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and ciprofloxacin-resistant MRSA isolates. Tested with isogenic methicillin-susceptible S. aureus (MSSA) and MRSA strains bearing quinolone-resistant target mutations, JNJ-Q2 displayed MICs ≤ 0.12 μg/ml, values 16- to 32-fold lower than those determined for moxifloxacin. Overexpression of the NorA efflux pump did not impact JNJ-Q2 MICs. Inhibition of S. aureus DNA gyrase and DNA topoisomerase IV enzymes demonstrated that JNJ-Q2 was more potent than comparators against wild-type enzymes and enzymes carrying quinolone-resistant amino acid substitutions, and JNJ-Q2 displayed equipotent activity against both enzymes. In serial-passage studies comparing resistance selection in parallel MRSA cultures by ciprofloxacin and JNJ-Q2, ciprofloxacin readily selected for mutants displaying MIC values of 128 to 512 μg/ml, which were observed within 18 to 24 days of passage. In contrast, cultures passaged in the presence of JNJ-Q2 displayed MICs ≤ 1 μg/ml for a minimum of 27 days of serial passage. A mutant displaying a JNJ-Q2 MIC of 4 μg/ml was not observed until after 33 days of passage. Mutant characterization revealed that ciprofloxacin-passaged cultures with MICs of 256 to 512 μg/ml carried only 2 or 3 quinolone resistance-determining region (QRDR) mutations. Cultures passaged with JNJ-Q2 selection for up to 51 days displayed MICs of 1 to 64 μg/ml and carried between 4 and 9 target mutations. Established in vitro biofilms of wild-type or ciprofloxacin-resistant MRSA exposed to JNJ-Q2 displayed greater decreases in bacterial counts (7 days of exposure produced 4.5 to >7 log(10) CFU decreases) than biofilms exposed to ciprofloxacin, moxifloxacin, rifampin, or vancomycin.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, LLC, Raritan, New Jersey 08869, USA. BMorrow@its.jnj.com
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Morrow
authors.forename: Darren
authors.initials: D
authors.lastname: Abbanat
authors.forename: Ellen Z
authors.initials: EZ
authors.lastname: Baum
authors.forename: Steven M
authors.initials: SM
authors.lastname: Crespo-Carbone
authors.forename: Todd A
authors.initials: TA
authors.lastname: Davies
authors.forename: Wenping
authors.initials: W
authors.lastname: He
authors.forename: Wenchi
authors.initials: W
authors.lastname: Shang
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Queenan
authors.forename: A Simon
authors.initials: AS
authors.lastname: Lynch
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D002939:Ciprofloxacin / Q000494:pharmacology; D027081:DNA Gyrase / Q000235:genetics; D027101:DNA Topoisomerase IV / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics; D024841:Fluoroquinolones / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008712:Methicillin / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests / Q000706:statistics & numerical data; D009154:Mutation; D012692:Serial Passage; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development
chemical_list: C550935:7-(3-(2-amino-1-fluoroethylidene)-1-piperidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid; D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D002939:Ciprofloxacin; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase; D008712:Methicillin