Antistaphylococcal Activities of the New Fluoroquinolone JNJ-Q2

• Published in: Antimicrobial Agents and Chemotherapy 2011-12, Vol.55 (12), p.5512-5521
• Main Authors: Morrow, Brian J, Abbanat, Darren, Baum, Ellen Z, Crespo-Carbone, Steven M, Davies, Todd A, He, Wenping, Shang, Wenchi, Queenan, Anne Marie, Lynch, A. Simon
• Format: Article
• Language: English
• Subjects: amino acid substitution; Anti-Bacterial Agents; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; antibacterial properties; antibiotic resistance; Antibiotics. Antiinfectious agents. Antiparasitic agents; biofilm; Biofilms - drug effects; Biofilms - growth & development; Biological and medical sciences; ciprofloxacin; Ciprofloxacin - pharmacology; DNA Gyrase - genetics; DNA topoisomerase; DNA topoisomerase (ATP-hydrolysing); DNA Topoisomerase IV - genetics; Drug Resistance, Bacterial - genetics; Fluoroquinolones; Fluoroquinolones - chemistry; Fluoroquinolones - pharmacology; Humans; Mechanisms of Action: Physiological Effects; Medical sciences; Methicillin - pharmacology; Methicillin-Resistant Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - growth & development; Microbial Sensitivity Tests - statistics & numerical data; minimum inhibitory concentration; mutants; Mutation; Pharmacology. Drug treatments; plate count; Serial Passage; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - growth & development; transporters; vancomycin
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.00470-11

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 log10 CFU decreases) than biofilms exposed to ciprofloxacin, moxifloxacin, rifampin, or vancomycin.