Activity of non-fluorinated quinolones (NFQs) against quinolone-resistant Escherichia coli and Streptococcus pneumoniae

• Published in: Journal of antimicrobial chemotherapy Vol. 48; no. 1; pp. 29 - 36
• Main Authors: Roychoudhury, Siddhartha, Twinem, Tracy L., Makin, Kelly M., McIntosh, Eric J., Ledoussal, Benoit, Catrenich, Carl E.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.07.2001; Oxford Publishing Limited (England)
• Subjects: Anti-Infective Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; DNA Gyrase; DNA Topoisomerase IV; DNA Topoisomerases, Type II - genetics; Drug Resistance, Microbial; Escherichia coli - drug effects; Fluoroquinolones; Medical sciences; Microbial Sensitivity Tests; Pharmacology. Drug treatments; Streptococcus pneumoniae - drug effects; Topoisomerase II Inhibitors; Human; DNA topoisomerase (ATP-hydrolysing); Enzyme; Escherichia coli; In vitro; Biological activity; Streptococcus pneumoniae; Resistance; Streptococcaceae; Fluoroquinolone derivatives; Isomerases; Sensitivity resistance; Enzymatic activity; Bacteria; Genetics; Micrococcales; Mutation; Antibacterial agent; Mechanism of action; Clinical isolate; Quinolone derivatives; Enterobacteriaceae
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/48.1.29

The newly developed 8-methoxy, non-fluorinated quinolones (NFQs) were studied to elucidate their enzyme inhibitory activity against wild-type and mutant GyrA (Ser-83→Trp) forms of Escherichia coli DNA gyrase. Using a DNA supercoiling inhibition assay, the NFQs were found to inhibit 50% (IC50) of the E. coli DNA gyrase activity in the 1.6–3.2 mg/L concentration range and were comparable to ciprofloxacin. However, against the GyrA (Ser-83→Trp) mutant, the NFQs were ~16-fold more potent than ciprofloxacin. Antibacterial potency of the NFQs was investigated using clinical isolates of E. coli and penicillin-resistant Streptococcus pneumoniae (PRSP), including strains with reduced susceptibility to quinolones. Against 20 uncharacterized clinical isolates of E. coli, the MIC90s of the NFQs were in the 0.125–0.25 mg/L range while those of ciprofloxacin, trovafloxacin, gatifloxacin and clinafloxacin were in the 0.016–0.125 mg/L range. Against clinical isolates with characterized mutations in gyrA and parC, PGE9262932, an NFQ, was two- to eight-fold more potent than ciprofloxacin. Against 23 clinical isolates of PRSP, the NFQs (MIC90 0.031–0.125 mg/L) were more potent than ciprofloxacin, trovafloxacin, and gatifloxacin (MIC90 0.25–2.0 mg/L), and at least as potent as clinafloxacin (MIC90 0.125 mg/L). Against S. pneumoniae strains with gyrA and parC mutations, the NFQs (MIC 0.125–1.0 mg/L) were more potent than ciprofloxacin, trovafloxacin and gatifloxacin (MIC 4–32 mg/L), and comparable to clinafloxacin (MIC 0.5–1 mg/L).