An FtsZ-Targeting Prodrug with Oral Antistaphylococcal Efficacy In Vivo
An FtsZ-Targeting Prodrug with Oral Antistaphylococcal Efficacy In Vivo
复制标题
DOI：
10.1128/aac.01016-13
复制
发表时间：
2013-12-01
影响因子：
4.9
通讯作者：
Pilch, Daniel S.
中科院分区：
文献类型：
--
作者：
Kaul, Malvika;Mark, Lilly;Pilch, Daniel S.
细菌细胞分裂蛋白FtsZ代表了一种新的抗生素靶标，尚未在临床上开发。苯甲酰胺PC 190723是在鼠感染模型系统中表现出体内功效的首批FtsZ靶向化合物之一。尽管其最初的承诺，该化合物的不良制剂特性限制了其临床开发的潜力。我们在这里描述了一个N-曼尼希碱衍生物的PC 190723与增强的药物样特性和口服体内疗效的发展。N-曼尼希碱衍生物（TXY 436）在适于口服体内给药的酸性水性载体（10 mM柠檬酸盐，pH 2.6）中的溶解度类似于PC 190723的100倍。在生理pH值（7.4），TXY 436作为一种前药，转化为PC 190723的转换半衰期为18.2 +/- 1.6分钟。药代动力学分析后，静脉注射给药的TXY 436到小鼠产生的TXY 436前药和PC 190723产品的消除半衰期分别为0.26和0.96小时。此外，发现TXY 436是口服生物可利用的，并且与显著的血管外分布相关。采用甲氧西林敏感金黄色葡萄球菌或耐甲氧西林金黄色葡萄球菌全身感染小鼠模型。金黄色葡萄球菌，我们表明TXY 436在口服给药后在体内有效。相比之下，PC 190723的口服给药无效。使用Vero细胞对TXY 436进行的哺乳动物细胞毒性研究显示，在化合物浓度至少为抗葡萄球菌活性的64倍时，没有毒性。这些共同的性质使TXY 436成为一个值得进一步研究的候选者，作为一种临床上有用的药物，用于治疗葡萄球菌感染。
The bacterial cell division protein FtsZ represents a novel antibiotic target that has yet to be exploited clinically. The benzamide PC190723 was among the first FtsZ-targeting compounds to exhibit in vivo efficacy in a murine infection model system. Despite its initial promise, the poor formulation properties of the compound have limited its potential for clinical development. We describe here the development of an N-Mannich base derivative of PC190723 with enhanced drug-like properties and oral in vivo efficacy. The N-Mannich base derivative (TXY436) is similar to 100-fold more soluble than PC190723 in an acidic aqueous vehicle (10 mM citrate, pH 2.6) suitable for oral in vivo administration. At physiological pH (7.4), TXY436 acts as a prodrug, converting to PC190723 with a conversion half-life of 18.2 +/- 1.6 min. Pharmacokinetic analysis following intravenous administration of TXY436 into mice yielded elimination half-lives of 0.26 and 0.96 h for the TXY436 prodrug and its PC190723 product, respectively. In addition, TXY436 was found to be orally bioavailable and associated with significant extravascular distribution. Using a mouse model of systemic infection with methicillin-sensitive Staphylococcus aureus or methicillin-resistant S. aureus, we show that TXY436 is efficacious in vivo upon oral administration. In contrast, the oral administration of PC190723 was not efficacious. Mammalian cytotoxicity studies of TXY436 using Vero cells revealed an absence of toxicity up to compound concentrations at least 64 times greater than those associated with antistaphylococcal activity. These collective properties make TXY436 a worthy candidate for further investigation as a clinically useful agent for the treatment of staphylococcal infections.