School of Chemical Engineering and Technology, Guangdong Engineering Technology Research Center for Platform Chemicals from Marine Biomass and Their Functionalization, Sun Yat-sen University, Zhuhai 519082, PR China.
School of Chemical Engineering and Technology, Guangdong Engineering Technology Research Center for Platform Chemicals from Marine Biomass and Their Functionalization, Sun Yat-sen University, Zhuhai 519082, PR China.
Bioorg Chem. 2024 Jun;147:107328. doi: 10.1016/j.bioorg.2024.107328. Epub 2024 Apr 3.
Discovering novel NDM-1 inhibitors is an urgent task for treatment of 'superbug' infectious diseases. In this study, we found that naturally occurring houttuynin and its sulfonate derivatives might be effective NDM-1 inhibitors with novel mechanism, i.e. the attribute of partially covalent inhibition of sulfonate derivatives of houttuynin against NDM-1. Primary structure-activity relationship study showed that both the long aliphatic side chain and the warhead of aldehyde group are vital for the efficiency against NDM-1. The homologs with longer chains (SNH-2 to SNH-5) displayed stronger inhibitory activities with IC range of 1.1-1.5 μM, while the shorter chain the weaker inhibition. Further synergistic experiments in cell level confirmed that all these 4 compounds (at 32 μg/mL) recovered the antibacterial activity of meropenem (MER) against E. coli BL21/pET15b-bla.
发现新型 NDM-1 抑制剂是治疗“超级细菌”传染病的当务之急。在这项研究中，我们发现天然存在的鱼腥草素及其磺酸盐衍生物可能是具有新型机制的有效 NDM-1 抑制剂，即磺酸盐衍生物对 NDM-1 的部分共价抑制特性。初步的构效关系研究表明，脂肪族侧链的长度和醛基的弹头都是对 NDM-1 高效性的关键。具有更长链的同系物（SNH-2 到 SNH-5）显示出更强的抑制活性，IC 范围为 1.1-1.5 μM，而较短的链则抑制较弱。在细胞水平的进一步协同实验证实，所有这 4 种化合物（在 32 μg/mL 时）都恢复了美罗培南（MER）对 BL21/pET15b-bla 大肠杆菌的抗菌活性。
