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Aspergillomarasmine A overcomes metallo-beta-lactamase antibiotic resistance

King, Andrew M., Reid-Yu, Sarah A., Wang, Wenliang, King, Dustin T., De Pascale, Gianfranco, Strynadka, Natalie C., Walsh, Timothy Rutland, Coombes, Brian K. and Wright, Gerard D. 2014. Aspergillomarasmine A overcomes metallo-beta-lactamase antibiotic resistance. Nature 510 (7506) , pp. 503-506. 10.1038/nature13445

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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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: Nature Publishing Group
Last Modified: 07 Feb 2019 11:28
URI: http://orca.cf.ac.uk/id/eprint/87626

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