Nature. 2014 Jun 26;510(7506):503-6. doi: 10.1038/nature13445.

Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance.

King AM¹, Reid-Yu SA², Wang W³, King DT⁴, De Pascale G³, Strynadka NC⁴, Walsh TR⁵, Coombes BK², Wright GD⁶.

Author information

1: 1] M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada [2] Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
2: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
3: M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
4: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
5: Cardiff Institute of Infection & Immunity, Cardiff University, Cardiff CF14 4XN, UK.
6: 1] M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada [2] Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4K1, Canada [3] Department of Biochemistry and Biomedical Sciences, 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.