Novel partially reversible NDM-1 inhibitors based on the naturally occurring houttuynin
Lifang Wang1, Yaowen Liang1, Pan Luo1
1School 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.
Abstract:
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 IC50 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-blaNDM-1.
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