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

Hongzhe Sun (), Qi Zhang, Runming Wang (), Haibo Wang, Yuen-Ting Wong, Minji Wang, Quan Hao, Aixin Yan, Richard Yi-Tsun Kao, Pak-Leung Ho and Hongyan Li
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Hongzhe Sun: The University of Hong Kong
Qi Zhang: The University of Hong Kong
Runming Wang: The University of Hong Kong
Haibo Wang: The University of Hong Kong
Yuen-Ting Wong: The University of Hong Kong
Minji Wang: The University of Hong Kong
Quan Hao: The University of Hong Kong
Aixin Yan: The University of Hong Kong
Richard Yi-Tsun Kao: The University of Hong Kong
Pak-Leung Ho: The University of Hong Kong
Hongyan Li: The University of Hong Kong

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18939-y

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