Novel bacterial acetyl coenzyme a carboxylase inhibitors with antibiotic efficacy in vivo
Novel bacterial acetyl coenzyme a carboxylase inhibitors with antibiotic efficacy in vivo
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DOI：
10.1128/aac.00012-06
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发表时间：
2006-08-01
影响因子：
4.9
通讯作者：
Ziegelbauer, K.
中科院分区：
文献类型：
--
作者：
Freiberg, C.;Pohlmann, J.;Ziegelbauer, K.
最近发现假肽吡咯烷二酮抗生素，如moiramide B，靶向细菌的多亚基乙酰辅酶A（乙酰辅酶A）羧化酶。在本文中，我们描述了模块化组成的吡咯烷二酮的每个部分的合成变化，提供深入了解生化靶标活性，体外效价和体内功效的结构-活性关系。与之前报道的变体相比，这些新型衍生物对革兰氏阳性细菌的活性显着提高。该化合物对广谱金黄色葡萄球菌临床分离株的MIC 90值为0.1 μ g/ml。未观察到与目前临床实践中使用的抗生素的交叉耐药性。由吡咯烷二酮诱导的抗性突变仅位于细菌乙酰辅酶A羧化酶的羧基转移酶亚基中，表明所有测试的衍生物的作用机制相同。通过盐的形成实现了物理化学特征的改善，导致高达5克/升的水溶解度。首次将该化合物类的体外活性与其体内功效进行了比较，证明了从体内活性较弱的化合物到具有显著功效的药物的途径。在S.金黄色葡萄球菌脓毒症中，报告的最佳化合物的100%有效剂量为25 mg/kg体重，仅比对照分子利奈唑胺高4倍。通过化学衍生化实现的明显改善反映了这种新型抗生素化合物类别用于未来治疗的潜力。
The pseudopeptide pyrrolidinedione antibiotics, such as moiramide B, have recently been discovered to target the multisubunit acetyl coenzyme A (acetyl-CoA) carboxylases of bacteria. In this paper, we describe synthetic variations of each moiety of the modularly composed pyrrolidinediones, providing insight into structure-activity relationships of biochemical target activity, in vitro potency, and in vivo efficacy. The novel derivatives showed highly improved activities against gram-positive bacteria compared to those of previously reported variants. The compounds exhibited a MIC90 value of 0.1 mu g/ml against a broad spectrum of Staphylococcus aureus clinical isolates. No cross-resistance to antibiotics currently used in clinical practice was observed. Resistance mutations induced by pyrrolidinediones are exclusively located in the carboxyltransferase subunits of the bacterial acetyl-CoA carboxylase, indicating the identical mechanisms of action of all derivatives tested. Improvement of the physicochemical profile was achieved by salt formation, leading to aqueous solubilities of up to 5 g/liter. For the first time, the in vitro activity of this compound class was compared with its in vivo efficacy, demonstrating a path from compounds weakly active in vivo to agents with significant efficacy. In a murine model of S. aureus sepsis, the 100% effective dose of the best compound reported was 25 mg/kg of body weight, only fourfold higher than that of the comparator molecule linezolid. The obvious improvements achieved by chemical derivatization reflect the potential of this novel antibiotic compound class for future therapy.