期刊
NATURE
卷 510, 期 7506, 页码 503-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13445
关键词
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资金
- UK Medical Research Council [G1100135]
- Canadian Institutes of Health Research [MT-13536]
- Natural Sciences and Engineering Research Council [237480]
- Canada Research Chair in Infectious Disease Pathogenesis
- Antibiotic Biochemistry
- MRC [G1100135] Funding Source: UKRI
- Medical Research Council [G1100135] Funding Source: researchfish
The emergence and spread of carbapenem-resistant Gram-negative pathogens is a global public health problem. The acquisition of metallo-beta-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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