4′-Phosphopantetheinyl transferases (PPTases) catalyze a post-translational modification essential to bacterial cell viability and virulence. We present the discovery and medicinal chemistry optimization of 2-pyridinyl-N-(4-aryl)piperazine-1-carbothioamides, which exhibit submicromolar inhibition of bacterial Sfp-PPTase with no activity toward the human orthologue. Moreover, compounds within this class possess antibacterial activity in the absence of a rapid cytotoxic response in human cells. An advanced analogue of this series, ML267 (55), was found to attenuate production of an Sfp-PPTase-dependent metabolite when applied to Bacillus subtilis at sublethal doses. Additional testing revealed antibacterial activity against methicillin-resistant Staphylococcus aureus, and chemical genetic studies implicated efflux as a mechanism for resistance in Escherichia coli. Additionally, we highlight the in vitro absorption, distribution, metabolism, and excretion and in vivo pharmacokinetic profiles of compound 55 to further demonstrate the potential utility of this small-molecule inhibitor.

中文翻译：

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4-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide (ML267)，一种抑制二次代谢的细菌磷酸酯基转移酶的强效抑制剂并阻碍细菌生长

4'-磷酸酯基转移酶 (PPTases) 催化对细菌细胞活力和毒力至关重要的翻译后修饰。我们展示了 2- pyridinyl- N- (4-aryl)piperazine-1-carbothioamides的发现和药物化学优化，它表现出对细菌 Sfp-PPTase 的亚微摩尔抑制，对人类直向同源物没有活性。此外，此类化合物在人体细胞中没有快速细胞毒性反应的情况下具有抗菌活性。该系列的高级类似物 ML267 ( 55 ) 当以亚致死剂量应用于枯草芽孢杆菌时，可以减弱 Sfp-PPTase 依赖性代谢物的产生。额外的测试显示对耐甲氧西林的抗菌活性金黄色葡萄球菌和化学遗传学研究表明外排是大肠杆菌耐药的一种机制。此外，我们强调了化合物55 的体外吸收、分布、代谢和排泄以及体内药代动力学特征，以进一步证明这种小分子抑制剂的潜在效用。