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

Abstract

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 approximately 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).

Pharmacokinetics and Pharmacodynamics of Nemonoxacin against Streptococcus pneumoniae in an In Vitro Infection Model

“…emonoxacin, a novel nonfluorinated quinolone, exerts broad antibacterial activity by interrupting DNA synthesis in prokaryotic organisms (1). The antimicrobial spectrum includes Gram-positive and Gram-negative bacteria as well as atypical pathogens such as penicillin-resistant Streptococcus pneumoniae and methicillin-and vancomycin-resistant Staphylococcus aureus (2,3).…”

In Vivo Efficacies and Pharmacokinetics of DX-619, a Novel Des-Fluoro(6) Quinolone, against Streptococcus pneumoniae in a Mouse Lung Infection Model

“…Roychoudhury et al (22) developed 8-methoxy, nonfluorinated quinolones and reported that the nonfluorinated quinolones were less affected in vitro by preexisting and characterized target mutations that reduce the potencies of quinolones against S. pneumoniae. DX-619 may also have potent efficacy against ciprofloxacin-resistant S. pneumoniae, but further evaluation is needed.…”

Development and Validation of a Whole-Cell Inhibition Assay for Bacterial Methionine Aminopeptidase by Surface-Enhanced Laser Desorption Ionization-Time of Flight Mass Spectrometry

“…The MICs were determined as described previously (11). Briefly, bacterial cultures (5 ϫ 10 5 CFU/ml) were incubated overnight in brain heart infusion (BHI) broth in the presence of test compounds in duplicate samples in a twofold broth dilution series.…”