RESUMEN
We previously demonstrated that piperazinyl-linked fluoroquinolone dimers possess potent antibacterial activity against drug-resistant strains of Staphylococcus aureus. In this study, we report the preparation and evaluation of a series of incomplete dimers toward ascertaining structural features of piperazinyl-linked ciprofloxacin dimers that render these agents refractory to fluoroquinolone-resistance mechanisms in Staphylococcus aureus.
Asunto(s)
Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Ciprofloxacina/síntesis química , Ciprofloxacina/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Antiinfecciosos/química , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Ciprofloxacina/química , ADN Bacteriano/efectos de los fármacos , Farmacorresistencia Bacteriana , Mutación/genética , Ácido Pipemídico/síntesis química , Ácido Pipemídico/farmacología , Piperazinas/química , Staphylococcus aureus/enzimología , Staphylococcus aureus/genética , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I , Inhibidores de Topoisomerasa IIRESUMEN
The synthesis of symmetric and asymmetric piperazinyl-linked dimers of the fluoroquinolone class of antibiotics is described. Specific dimers are shown to possess potent antibacterial activity against drug-resistant strains of Staphylococcus aureus, including strains possessing resistance due to the NorA multidrug efflux pump and a mutation in the quinolone resistance-determining region of topoisomerase IV.
Asunto(s)
Antibacterianos/síntesis química , Fluoroquinolonas/síntesis química , Fluoroquinolonas/farmacología , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/farmacología , Proteínas Bacterianas , Reactivos de Enlaces Cruzados/química , Topoisomerasa de ADN IV/genética , Dimerización , Farmacorresistencia Bacteriana , Pruebas de Sensibilidad Microbiana , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Piperazinas/química , Relación Estructura-ActividadRESUMEN
Daptomycin exhibits in vitro bactericidal activity against clinically significant gram-positive bacteria. We employed pharmacodynamic modeling to determine a once-daily dosing regimen of daptomycin that correlates to pharmacodynamic endpoints for different resistant gram-positive clinical strains. An in vitro pharmacodynamic model with an initial inoculum of 6 log(10) CFU/ml was used to simulate daptomycin regimens ranging in dose from 0 to 9 mg/kg of body weight/day, with corresponding exposures reflecting free-daptomycin concentrations in serum. Bacterial density was profiled over 48 h for two methicillin-resistant Staphylococcus aureus (MRSA-67 and -R515), two glycopeptide intermediate-resistant S. aureus (GISA-992 and -147398), and two vancomycin-resistant Enterococcus faecium (VREF-12366 and -SF12047) strains. A sigmoid dose-response model was used to estimate the effective dose required to achieve 50% (ED(50)) and 80% (ED(80)) bacterial density reduction at 48 h. Daptomycin MICs for study isolates ranged from 0.125 to 4 micro g/ml. Model fitting resulted in an r(2) of >0.80 for all tested isolates. Control growths at 48 h ranged from 7.3 to 8.5 log(10) CFU/ml. Sigmoid relationships were not superimposable between categorical resistant species: ED(50) and ED(80) values were 1.9 and 3.1, 4.2 and 5.6, and 5.4 and 6.8 mg/kg for MRSA, GISA, and VREF isolates, respectively. Doses required to achieve ED(50) and ED(80) values correlated with MIC differences between tested organisms. Corresponding area under the concentration-time curve from 0 to 24 h/MIC exposure ratios demonstrated a wide range of ED(80) values among the tested isolates. Doses ranging between 3 and 7 mg/kg produced significant bactericidal activity (ED(80)) against these multidrug-resistant S. aureus and E. faecium isolates.