2. Academic Validation
  3. Resensitizing carbapenem- and colistin-resistant bacteria to antibiotics using auranofin

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

  • Nat Commun. 2020 Oct 16;11(1):5263. doi: 10.1038/s41467-020-18939-y.
Hongzhe Sun 1 2 3,  Qi Zhang 4,  Runming Wang 5,  Haibo Wang 4,  Yuen-Ting Wong 4 6,  Minji Wang 7,  Quan Hao 8,  Aixin Yan 7,  Richard Yi-Tsun Kao 6 9 10,  Pak-Leung Ho 6 9 10,  Hongyan Li 4
Affiliations

Affiliations

  • 1 Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, SAR, China. hsun@hku.hk.
  • 2 State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, SAR, China. hsun@hku.hk.
  • 3 CAS-HKU Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong, The University of Hong Kong, Pokfulam Road, Hong Kong, SAR, China. hsun@hku.hk.
  • 4 Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, SAR, China.
  • 5 Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, SAR, China. u3002771@connect.hku.hk.
  • 6 Department of Microbiology, The University of Hong Kong, Sassoon Road, Hong Kong, SAR, China.
  • 7 School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong, SAR, China.
  • 8 School of Biomedical Sciences, The University of Hong Kong, Sassoon Road, Hong Kong, SAR, China.
  • 9 State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, SAR, China.
  • 10 The Research Centre of Infection and Immunology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
PMID: 33067430 DOI: 10.1038/s41467-020-18939-y
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.

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