Resensitizing carbapenem- and colistin-resistant bacteria to antibiotics using auranofin

Hongzhe Sun,Richard Yi-Tsun Kao,Pak-Leung Ho,Qi Zhang,Runming Wang,Yuen-Ting Wong,Haibo Wang,Minji Wang,Hongyan Li,Quan Hao,Aixin Yan

doi:10.1038/s41467-020-18939-y

Hongzhe Sun, Richard Yi-Tsun Kao + Show 9 more

Open Access

https://doi.org/10.1038/s41467-020-18939-y

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Abstract

Global emergence of Gram-negative bacteria carrying the plasmid-borne resistance genes, blaMBL and mcr, raises a significant challenge to the treatment of life-threatening infections by the antibiotics, carbapenem and colistin (COL). Here, we identify an antirheumatic drug, auranofin (AUR) as a dual inhibitor of metallo-β-lactamases (MBLs) and mobilized colistin resistance (MCRs), two resistance enzymes that have distinct structures and substrates. We demonstrate that AUR irreversibly abrogates both enzyme activity via the displacement of Zn(II) cofactors from their active sites. We further show that AUR synergizes with antibiotics on killing a broad spectrum of carbapenem and/or COL resistant bacterial strains, and slows down the development of β-lactam and COL resistance. Combination of AUR and COL rescues all mice infected by Escherichia coli co-expressing MCR-1 and New Delhi metallo-β-lactamase 5 (NDM-5). Our findings provide potential therapeutic strategy to combine AUR with antibiotics for combating superbugs co-producing MBLs and MCRs.

Highlights

Global emergence of Gram-negative bacteria carrying the plasmid-borne resistance genes, blaMBL and mcr, raises a significant challenge to the treatment of life-threatening infections by the antibiotics, carbapenem and colistin (COL)
Our results showed that AUR irreversibly inhibit New Delhi metallo-β-lactamase 1 (NDM-1) activity and disrupted the function of mobilized colistin resistance (MCRs)-1 via displacing Zn(II) ions in the active sites and forming Au-NDM1 or Au-MCR-1
A primary screening on a battery of metal compounds was performed to seek for COL and/or carbapenem synergism against E. coli CKE, a clinical isolate that co-produced New Delhi metallo-βlactamase 5 (NDM-5) and MCR-1 (MICCOL = 8 μg·mL−1, MICMER = 32 μg·mL−1)

Summary

Introduction

Global emergence of Gram-negative bacteria carrying the plasmid-borne resistance genes, blaMBL and mcr, raises a significant challenge to the treatment of life-threatening infections by the antibiotics, carbapenem and colistin (COL). Combination of AUR and COL rescues all mice infected by Escherichia coli co-expressing MCR-1 and New Delhi metallo-βlactamase 5 (NDM-5). Our findings provide potential therapeutic strategy to combine AUR with antibiotics for combating superbugs co-producing MBLs and MCRs. 1234567890():,; The clinical efficacy of antibiotics has been severely challenged by plasmid-borne resistance determinants, in particular carbapenemase that renders Gram-negative bacteria resistant to carbapenem therapy, in either hospital or community settings, triggering the onset of the worldwide antimicrobial resistance crisis[1].

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