Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance

Andrew M. King, Sarah A. Reid-Yu, Wenliang Wang, Dustin T. King, Gianfranco De Pascale, Natalie C. Strynadka, Timothy R. Walsh, Brian K. Coombes and Gerard D. Wright ()
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Andrew M. King: M.G. DeGroote Institute for Infectious Disease Research, 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

Nature, 2014, vol. 510, issue 7506, 503-506

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13445

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