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

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Sun H,Zhang Q,Wang R,Wang H,Wong YT,Wang M,Hao Q,Yan A,Kao RY,Ho PL,Li H

doi

10.1038/s41467-020-18939-y

subject

Has Abstract

pub_date

2020-10-16 00:00:00

pages

5263

issue

1

issn

2041-1723

pii

10.1038/s41467-020-18939-y

journal_volume

11

pub_type

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