An Improved Small-Molecule Inhibitor of FtsZ with Superior In Vitro Potency, Drug-Like Properties, and In Vivo Efficacy
An Improved Small-Molecule Inhibitor of FtsZ with Superior In Vitro Potency, Drug-Like Properties, and In Vivo Efficacy
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DOI：
10.1128/aac.01580-12
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发表时间：
2013-01-01
影响因子：
4.9
通讯作者：
Haydon, David J.
中科院分区：
文献类型：
--
作者：
Stokes, Neil R.;Baker, Nicola;Haydon, David J.
细菌细胞分裂蛋白FtsZ是小分子抗菌药物开发的重要靶点。3-甲氧基苯甲酰胺的衍生物，包括化合物PC190723，已被报道为有效和选择性的抗葡萄球菌药物，通过破坏细胞内FtsZ功能发挥作用。在这里，我们报告了3-甲氧基苯甲酰胺衍生物对候选药物的进一步优化。描述了一种更先进的先导化合物的体外和体内表征，命名为化合物1。化合物1具有较强的抗菌活性，对所有葡萄球菌，包括耐甲氧西林和多药耐药的金黄色葡萄球菌和表皮葡萄球菌，平均MIC为0.12微克/毫升。化合物1抑制了一株携带FtsZ中G196A突变的金黄色葡萄球菌，该突变使其对PC190723产生抗药性。与PC190723一样，化合物1通过阻断胞质分裂作用于整个细菌细胞。在棋盘实验中，化合物1与多种抗生素之间没有相互作用。化合物1表现出良好的体外药理性质和良好的体内药代动力学特征，在小鼠体内的生物利用度为82.0%。化合物1在系统性金黄色葡萄球菌感染的小鼠模型中显示出疗效，并在大腿感染模型中显著降低了细菌负荷。使用被命名为化合物2的化合物1的琥珀酸酯前药，从感染的大腿中恢复的金黄色葡萄球菌细胞数量比从对照中恢复的金黄色葡萄球菌细胞数量减少得更多，相当于3.68个对数单位。总而言之，优化的3-甲氧基苯甲酰胺衍生物可能会产生一种用于治疗耐药葡萄球菌感染的一流FtsZ抑制剂。
The bacterial cell division protein FtsZ is an attractive target for small-molecule antibacterial drug discovery. Derivatives of 3-methoxybenzamide, including compound PC190723, have been reported to be potent and selective antistaphylococcal agents which exert their effects through the disruption of intracellular FtsZ function. Here, we report the further optimization of 3-methoxybenzamide derivatives towards a drug candidate. The in vitro and in vivo characterization of a more advanced lead compound, designated compound 1, is described. Compound 1 was potently antibacterial, with an average MIC of 0.12 mu g/ml against all staphylococcal species, including methicillin- and multidrug-resistant Staphylococcus aureus and Staphylococcus epidermidis. Compound 1 inhibited an S. aureus strain carrying the G196A mutation in FtsZ, which confers resistance to PC190723. Like PC190723, compound 1 acted on whole bacterial cells by blocking cytokinesis. No interactions between compound 1 and a diverse panel of antibiotics were measured in checkerboard experiments. Compound 1 displayed suitable in vitro pharmaceutical properties and a favorable in vivo pharmacokinetic profile following intravenous and oral administration, with a calculated bioavailability of 82.0% in mice. Compound 1 demonstrated efficacy in a murine model of systemic S. aureus infection and caused a significant decrease in the bacterial load in the thigh infection model. A greater reduction in the number of S. aureus cells recovered from infected thighs, equivalent to 3.68 log units, than in those recovered from controls was achieved using a succinate prodrug of compound 1, which was designated compound 2. In summary, optimized derivatives of 3-methoxybenzamide may yield a first-in-class FtsZ inhibitor for the treatment of antibiotic-resistant staphylococcal infections.