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

Lifang Wang; Yaowen Liang; Pan Luo; Manna Huang; Yiqian Wan

doi:10.1016/j.bioorg.2024.107328

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

Bioorg Chem. 2024 Jun:147:107328. doi: 10.1016/j.bioorg.2024.107328. Epub 2024 Apr 3.

Authors

Lifang Wang¹, Yaowen Liang¹, Pan Luo¹, Manna Huang², Yiqian Wan¹

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: huangmn25@mail.sysu.edu.cn.

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-bla_NDM-1.

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

MeSH terms

Anti-Bacterial Agents* / chemical synthesis
Anti-Bacterial Agents* / chemistry
Anti-Bacterial Agents* / pharmacology
Biological Products / chemical synthesis
Biological Products / chemistry
Biological Products / pharmacology
Dose-Response Relationship, Drug*
Escherichia coli Proteins
Escherichia coli* / drug effects
Escherichia coli* / enzymology
Humans
Microbial Sensitivity Tests*
Molecular Structure
Structure-Activity Relationship
beta-Lactamase Inhibitors / chemical synthesis
beta-Lactamase Inhibitors / chemistry
beta-Lactamase Inhibitors / pharmacology
beta-Lactamases / metabolism

Substances

beta-lactamase NDM-1
NDM-1 protein, E coli