Mode of action and resistance of the new fluoroquinolone BOL-303224-A

Abstract number: 1733_1161

Cambau E., Lepage J.F., Matrat S., Pan X.S., Roth dit Bettoni R., Corbel C., Daniel T., Darchy N., Aubry A., Lascols C., Fisher L.M.

Objectives: To investigate the mode of action and mechanisms of resistance to the new quinolone BOL-303224-A.

Methods: The new quinolone BOL-303224-A was investigated for (1) its inhibition of DNA gyrases and topoisomerases IV from Streptococcus pneumoniae, taken as the targeted bacterial species, and Escherichia coli, taken as the reference species, and induction of DNA cleavage by these type II topoisomerases, (2) mutations in the type II topoisomerase genes occurring in resistant mutants of S. pneumoniae, S. aureus and E. coli selected in vitro, and (3) activity on gyrase and topoisomerase IV defined mutants. These experiments were conducted in comparison to ciprofloxacin.

Results: At low concentrations, BOL-303224-A inhibited supercoiling activity of DNA gyrases of S. pneumoniae and E. coli (IC50s of 1 mg/L for both species) and decatenation by topoisomerase IV (IC50 of 0.4 and 10 mg/L, respectively), and induced formation of cleavable complexes at concentrations of 2.5 and 1 mM for DNA gyrase and topoisomerase IV of S. pneumoniae and 0.1 and 1.4 mM for those of E. coli, respectively. IC50s of BOL-303224-A were 5- to 16-fold lower than those of ciprofloxacin against pneumococcal topoisomerases. The main mechanism of resistance to SS734 was mutation in the DNA gyrase genes, mostly gyrA mutation at position 81, 83 and 87, but also gyrB mutation at positions 426 and 466 (numbering system used in E. coli). From the results on in vitro selection of resistant mutants, DNA gyrase was the primary target in E. coli, S. aureus and S. pneumoniae, and topoisomerase IV was the secondary target. However, a dual targeting is likely since the selection of resistant mutants of S. aureus could not be obtained in a single step and inhibitory concentrations were in the same range for DNA gyrase and topoisomerase IV of S. pneumoniae. MICs of BOL-303224-A were similarly affected by parC or gyrA mutations in the defined mutants of these two species, and they remained below 1 mg/mL in double gyrA-parC mutants of S. aureus and S. pneumoniae whereas ciprofloxacin MICs were up to >32 mg/L.

Conclusion: BOL-303224-A is a good inhibitor of bacterial type II topoisomerases in vitro, and is one of the rare quinolones to be as active against DNA gyrase as against topoisomerase IV of S. pneumoniae.

Session Details

Date: 31/03/2007
Time: 00:00-00:00
Session name: European Society of Clinical Microbiology and Infectious Diseases
Location: ICC, Munich, Germany
Presentation type:
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