Selection and Genetic Characterization of
            <i>Streptococcus pneumoniae</i>
            Mutants Resistant to the Des-F(6) Quinolone BMS-284756

supporting

confidence: 82%

Staphylococcus aureus Mutants Selected by BMS-284756

Discotto

Lawrence

DenBleyker

et al. 2001

“…Other nonfluorinated quinolones have also been reported to target both enzymes more evenly than ciprofloxacin, as evident from MIC studies performed with some of the same genetically defined mutants used in this study (39). MICs of garenoxacin for first-step topoisomerase IV or gyrase mutants (0.064 to 0.128 g/ml) are substantially below the drug concentrations achievable in serum after single doses of 400 and 800 mg (6.4 and 10.9 g/ml, respectively) (18). These findings suggest that the frequency of selection of resistant mutants from wild-type strains of S. aureus would be unlikely with the use of garenoxacin in clinical settings (22).…”

Section: Discussionmentioning

confidence: 87%

Dual Targeting of DNA Gyrase and Topoisomerase IV: Target Interactions of Garenoxacin (BMS-284756, T-3811ME), a New Desfluoroquinolone

İnce

Zhang

Silver

et al. 2002

We determined the target enzyme interactions of garenoxacin (BMS-284756, T-3811ME), a novel desfluoroquinolone, in Staphylococcus aureus by genetic and biochemical studies. We found garenoxacin to be four-to eightfold more active than ciprofloxacin against wild-type S. aureus. A single topoisomerase IV or gyrase mutation caused only a 2-to 4-fold increase in the MIC of garenoxacin, whereas a combination of mutations in both loci caused a substantial increase (128-fold). Overexpression of the NorA efflux pump had minimal effect on resistance to garenoxacin. With garenoxacin at twice the MIC, selection of resistant mutants (<7.4 ؋ 10 ؊12 to 4.0 ؋ 10 ؊11 ) was 5 to 6 log units less than that with ciprofloxacin. Mutations inside or outside the quinolone resistance-determining regions (QRDR) of either topoisomerase IV, or gyrase, or both were selected in single-step mutants, suggesting dual targeting of topoisomerase IV and gyrase. Three of the novel mutations were shown by genetic experiments to be responsible for resistance. Studies with purified topoisomerase IV and gyrase from S. aureus also showed that garenoxacin had similar activity against topoisomerase IV and gyrase (50% inhibitory concentration, 1.25 to 2.5 and 1.25 g/ml, respectively), and although its activity against topoisomerase IV was 2-fold greater than that of ciprofloxacin, its activity against gyrase was 10-fold greater. This study provides the first genetic and biochemical data supporting the dual targeting of topoisomerase IV and gyrase in S. aureus by a quinolone as well as providing genetic proof for the expansion of the QRDRs to include the 5 terminus of grlB and the 3 terminus of gyrA.

“…Most of the 11 isolates for which the MIC was 1 g/ml, however, had similar double mutations in ParC (Ser-79 to Phe and Lys-137 to Asn) and a single mutation in GyrA (either Ser-81 to Phe or Glu-85 to Lys). Some of these changes have been demonstrated in an in vitro resistance selection study (13) to produce low-level resistant mutants, with additional mutations in GyrA at Glu-85 and ParC at Asp-83 required to result in high-level resistance (MIC, 2 to 16 g/ml). Eight of the 11 strains were from Hong Kong.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial Activities of Garenoxacin (BMS 284756) against Asia-Pacific Region Clinical Isolates from the SENTRY Program, 1999 to 2001

Christiansen

Bell

Turnidge

et al. 2004

Between 1999 and 2001, 16,731 isolates from the Asia-Pacific Region were tested in the SENTRY Program for susceptibility to six fluoroquinolones including garenoxacin. Garenoxacin was four-to eightfold less active against Enterobacteriaceae than ciprofloxacin, although both drugs inhibited similar percentages at 1 g/ml. Garenoxacin was more active against gram-positive species than all other fluoroquinolones except gemifloxacin. For Staphylococcus aureus, oxacillin resistance was high in many participating countries (Japan, 67%; Taiwan, 60%; Hong Kong, 55%; Singapore, 52%), with corresponding high levels of ciprofloxacin resistance (57 to 99%) in oxacillin-resistant S. aureus (ORSA). Of the ciprofloxacin-resistant ORSA isolates, the garenoxacin MIC was >4 g/ml for only 9% of them. For Streptococcus pneumoniae, penicillin nonsusceptibility and macrolide resistance were high in many countries. No relationship was seen between penicillin and garenoxacin susceptibility, with all isolates being susceptible at <2 g/ml. There was, however, a partial correlation between ciprofloxacin and garenoxacin MICs. For ciprofloxacin-resistant isolates for which garenoxacin MICs were 0.25 to 1 g/liter, mutations in both the ParC and GyrA regions of the quinolone resistance-determining region could be demonstrated. No mutations conferring high-level resistance were detected. Garenoxacin shows useful activity against a wide range of organisms from the Asia-Pacific region. In particular, it has good activity against S. aureus and S. pneumoniae, although there is evidence that low-level resistance is present in those organisms with ciprofloxacin resistance.