In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: Microbiology profiling studies with staphylococci and streptococci
In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: Microbiology profiling studies with staphylococci and streptococci
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DOI：
10.1128/aac.01651-07
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发表时间：
2008-07-01
影响因子：
4.9
通讯作者：
Lynch, A. Simon
中科院分区：
文献类型：
--
作者：
Robertson, Gregory T.;Bonventre, Eric J.;Lynch, A. Simon
我们目前的数据，在体外进行的抗菌试验，涉及潜在的临床实用性的一种新的利福霉素-喹诺酮类杂合抗生素，CBR-2092，用于治疗革兰氏阳性球菌介导的感染。CBR-2092对300株葡萄球菌和链球菌临床分离株的MIC（90）为0.008 - 0.5 μ g/ml。针对金黄色葡萄球菌，CBR-2092表现出延长的抗生素后效应（PAEs）和亚MIC效应（SME），对于PAE（3x MIC）、SME（0.12x MIC）和PAE-SME（3x MIC/0.12x MIC）时期分别确定的值为3.2、6.5和> 8.5小时。研究了S.金黄色葡萄球菌表明CBR-2092不是诺拉或MepA外排泵的底物。在最小杀菌浓度和时间杀灭研究中，CBR-2092表现出对葡萄球菌的杀菌活性，保留对利福平或中间喹诺酮耐药菌株的杀菌活性，对利福平耐药菌株具有明显的自相矛盾的杀菌特性。在自发抗性研究中，CBR-2092表现出与其复合药效团的平衡贡献一致的活性，在琼脂中以1 μ g/ml测定的突变预防浓度为0.12 μ g/ml，抗性频率< 10（-12）。金黄色。同样，CBR-2092抑制了在高细胞密度下进行的时间杀灭研究中预先存在的利福霉素耐药性的出现。在研究S.金黄色葡萄球菌，CBR-2092表现出上级利福沙星、利福平以及利福沙星和利福平的混合物的延长的杀菌活性。总体而言，CBR-2092在体外进行的一系列抗微生物测定中表现出有希望的活性，这些测定涉及与有效治疗革兰氏阳性球菌介导的严重感染相关的性质。
We present data from antimicrobial assays performed in vitro that pertain to the potential clinical utility of a novel rifamycin-quinolone hybrid antibiotic, CBR-2092, for the treatment of infections mediated by gram-positive cocci. The MIC(90)s for CBR-2092 against 300 clinical isolates of staphylococci and streptococci ranged from 0.008 to 0.5 mu g/ml. Against Staphylococcus aureus, CBR-2092 exhibited prolonged postantibiotic effects (PAEs) and sub-MIC effects (SMEs), with values of 3.2, 6.5, and > 8.5 h determined for the PAE (3 x MIC), SME (0.12 x MIC), and PAE-SME (3 x MIC/0.12 x MIC) periods, respectively. Studies of genetically defined mutants of S. aureus indicate that CBR-2092 is not a substrate for the NorA or MepA efflux pumps. In minimal bactericidal concentration and time-kill studies, CBR-2092 exhibited bactericidal activity against staphylococci that was retained against rifampin- or intermediate quinolone-resistant strains, with apparent paradoxical cidal characteristics against rifampin-resistant strains. In spontaneous resistance studies, CBR-2092 exhibited activity consistent with balanced contributions from its composite pharmacophores, with a mutant prevention concentration of 0.12 mu g/ml and a resistance frequency of < 10(-12) determined at 1 mu g/ml in agar for S. aureus. Similarly, CBR-2092 suppressed the emergence of preexisting rifamycin resistance in time-kill studies undertaken at a high cell density. In studies of the intracellular killing of S. aureus, CBR-2092 exhibited prolonged bactericidal activity that was superior to the activities of moxifloxacin, rifampin, and a cocktail of moxifloxacin and rifampin. Overall, CBR-2092 exhibited promising activity in a range of antimicrobial assays performed in vitro that pertain to properties relevant to the effective treatment of serious infections mediated by gram-positive cocci.