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Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance

Author

Listed:
  • Andrew M. King

    (M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada
    McMaster University, Hamilton, Ontario L8S 4K1, Canada)

  • Sarah A. Reid-Yu

    (McMaster University, Hamilton, Ontario L8S 4K1, Canada)

  • Wenliang Wang

    (M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada)

  • Dustin T. King

    (University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada)

  • Gianfranco De Pascale

    (M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada)

  • Natalie C. Strynadka

    (University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada)

  • Timothy R. Walsh

    (Cardiff Institute of Infection & Immunity, Cardiff University, Cardiff CF14 4XN, UK)

  • Brian K. Coombes

    (McMaster University, Hamilton, Ontario L8S 4K1, Canada)

  • Gerard D. Wright

    (M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada
    McMaster University, Hamilton, Ontario L8S 4K1, Canada
    McMaster University, Hamilton, Ontario L8S 4K1, Canada)

Abstract

The emergence and spread of carbapenem-resistant Gram-negative pathogens is a global public health problem. The acquisition of metallo-β-lactamases (MBLs) such as NDM-1 is a principle contributor to the emergence of carbapenem-resistant Gram-negative pathogens that threatens the use of penicillin, cephalosporin and carbapenem antibiotics to treat infections. To date, a clinical inhibitor of MBLs that could reverse resistance and re-sensitize resistant Gram-negative pathogens to carbapenems has not been found. Here we have identified a fungal natural product, aspergillomarasmine A (AMA), that is a rapid and potent inhibitor of the NDM-1 enzyme and another clinically relevant MBL, VIM-2. AMA also fully restored the activity of meropenem against Enterobacteriaceae, Acinetobacter spp. and Pseudomonas spp. possessing either VIM or NDM-type alleles. In mice infected with NDM-1-expressing Klebsiella pneumoniae, AMA efficiently restored meropenem activity, demonstrating that a combination of AMA and a carbapenem antibiotic has therapeutic potential to address the clinical challenge of MBL-positive carbapenem-resistant Gram-negative pathogens.

Suggested Citation

  • Andrew M. King & Sarah A. Reid-Yu & Wenliang Wang & Dustin T. King & Gianfranco De Pascale & Natalie C. Strynadka & Timothy R. Walsh & Brian K. Coombes & Gerard D. Wright, 2014. "Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance," Nature, Nature, vol. 510(7506), pages 503-506, June.
    • Handle: RePEc:nat:nature:v:510:y:2014:i:7506:d:10.1038_nature13445
    DOI: 10.1038/nature13445
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