Novel partially reversible NDM-1 inhibitors based on the naturally occurring houttuynin

  • Bioorg Chem. 2024 Apr 3:147:107328. doi: 10.1016/j.bioorg.2024.107328.
Lifang Wang  1 ,  Yaowen Liang  1 ,  Pan Luo  1 ,  Manna Huang  2 ,  Yiqian Wan  1
Affiliations
  • 1. 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.
  • 2. 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. Electronic address: [email protected].
PMID: 38583248 DOI: 10.1016/j.bioorg.2024.107328
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.

Keywords
Houttuynin; Inhibitor; New Delhi metallo-β-lactamase (NDM-1); Superbug.
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