ROYCHOUDHURY S, MCINTOSH EJ, LEDOUSSAL B, CATRENICH CE; Interscience Conference on Antimicrobial Agents and Chemotherapy.
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 1999 Sep 26-29; 39: 304 (abstract no. 546).
Procter & Gamble Pharmaceuticals, Mason, OH
BACKGROUND: The objective of this work was to measure whole-cell inhibition of DNA gyrase (Gyrase) and topoisomerase IV (Topo IV) in Staphylococcus aureus by a series of non-fluoroquinolones (NFQs).METHODS: Using S. aureus strains with point mutations in the serine 80/ 84 hot spots of the target genes (gyrA and grlA), growth-based target inhibition potencies of three NFQs were estimated and compared with known fluoroquinolones.RESULTS: It was first shown that in a gyrA (Ser84-Leu) mutant, Topo IV was the target, while in strain MT5224c4 (grlA, Ser80-Phe), Gyrase was the target. Concentrations at which each of these agents caused 50% cell growth inhibition in strains SS1 and MT5224c4 were determined as a measure of Effective Target Inhibition (ETI[50]) for Topo IV and Gyrase, respectively. In the case of ciprofloxacin, gatifloxacin, trovafloxacin, and clinafloxacin, ETI[50]s were 0.05, 0.06, 0.006, and 0.009 microg/ml for Topo IV; and 0.5, 0.17, 0.1, and 0.028 microg/ml for Gyrase, respectively. The corresponding ETI[50]s for the NFQs were in 0.004-0.012 microg/ml range for Topo IV and in 0.014-0.05 microg/ml range for Gyrase.CONCLUSIONS: The NFQs and clinafloxacin have higher affinities against both Gyrase and Topo IV than ciprofloxacin, trovafloxacin, and gatifloxacin. The ETI[50] (Gyrase):ETI[50] (Topo IV) ratios are lower for the NFQs, gatifloxacin, and clinafloxacin (3-4) than for ciprofloxacin and trovafloxacin (10-16), suggesting that the former group of agents is better able to inhibit both the molecular targets simultaneously, thereby lowering the potential for resistance development in S. aureus via step-wise point mutations in the target genes.
Publication Types:
Keywords:
- Ciprofloxacin
- DNA Gyrase
- DNA Topoisomerase IV
- Fluoroquinolones
- Naphthyridines
- Staphylococcus aureus
- clinafloxacin
- gatifloxacin
- trovafloxacin
Other ID:
UI: 102246737
From Meeting Abstracts