Developing Pantetheinase-Resistant Pantothenamide Antibacterials: Structural Modification Impacts on PanK Interaction and Mode of Action,ACS Infectious Diseases

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Developing Pantetheinase-Resistant Pantothenamide Antibacterials: Structural Modification Impacts on PanK Interaction and Mode of Action
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-01-14 00:00:00 , DOI: 10.1021/acsinfecdis.7b00240
Leanne Barnard ₁ , Konrad J. Mostert ₁ , Willem A. L. van Otterlo ₂ , Erick Strauss ₁

Affiliation

Pantothenamides (PanAms) are analogues of pantothenate, the biosynthetic precursor of coenzyme A (CoA), and show potent antimicrobial activity against several bacteria and the malaria parasite in vitro. However, pantetheinase enzymes that normally degrade pantetheine in human serum also act on the PanAms, thereby reducing their potency. In this study, we designed analogues of the known antibacterial PanAm N-heptylpantothenamide (N7-Pan) to be resistant to pantetheinase by using three complementary structural modification strategies. We show that, while two of these are effective in imparting resistance, the introduced modifications have an impact on the analogues’ interaction with pantothenate kinase (PanK, the first CoA biosynthetic enzyme), which acts as a metabolic activator and/or target of the PanAms. This, in turn, directly affects their mode of action. Importantly, we discover that the phosphorylated version of N7-Pan shows pantetheinase resistance and antistaphylococcal activity, providing a lead for future studies in the ongoing search of PanAm analogues that show in vivo efficacy.

中文翻译：

开发耐泛素酶泛酸酰胺抗菌剂：结构修饰对PanK相互作用和作用方式的影响。

泛酰胺（PanAms）是泛酸的类似物，是辅酶A（CoA）的生物合成前体，在体外显示出对几种细菌和疟疾寄生虫的有效抗菌活性。但是，通常会降解人血清中泛酸的泛酸酶也作用于PanAms，从而降低了其效力。在这项研究中，我们设计了已知抗菌PanAm N的类似物-庚基泛酰胺（N7-Pan）通过使用三种互补的结构修饰策略对泛酶具有抗性。我们显示，尽管其中两个可有效地赋予抗性，但引入的修饰对类似物与泛酸激酶（PanK，第一个CoA生物合成酶）的相互作用有影响，泛酸激酶作为代谢活化剂和/或靶标的靶标PanAms。反过来，这直接影响他们的行动方式。重要的是，我们发现N7-Pan的磷酸化版本显示泛酶抗性和抗葡萄球菌活性，为正在进行的显示体内功效的PanAm类似物的未来研究提供了线索。

更新日期：2018-01-14

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