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.
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We thank M. Mulvey (Public Health Agency of Canada) and R. Melano (Public Health Ontario) for clinical strains. We thank L. Rossi for her work in constructing the screening strain. AMA inhibition activity on clinical strains by T.R.W. was funded by the UK Medical Research Council (G1100135). This research was funded by a Canadian Institutes of Health Research Grant (MT-13536), Natural Sciences and Engineering Research Council Grant (237480), and by a Canada Research Chair in Infectious Disease Pathogenesis (to B.K.C.) and Antibiotic Biochemistry (to G.D.W.).
The authors declare no competing financial interests.
Extended data figures and tables
a, b, Experiments were done as in Fig. 1b for ACE and CTX-M-15 (black circles), KPC-2 (white circles), and TEM-1 (black squares). Error bars denote standard deviation of at least two replicates.
CD-1 mice were infected with K. pneumoniae N11-2218 by i.p. injection. Mice were treated with either PBS (n = 6) or various doses of meropenem (n = 3 per group) by s.c. injection. Mice were euthanized 48 h after infection, and the bacterial load in the spleen was determined by selective plating. Data are the means with standard error.
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King, A., Reid-Yu, S., Wang, W. et al. Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance. Nature 510, 503–506 (2014). https://doi.org/10.1038/nature13445
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