King, Andrew M., Reid-Yu, Sarah A., Wang, Wenliang, King, Dustin T., De Pascale, Gianfranco, Strynadka, Natalie C., Walsh, Timothy R.  ORCID: https://orcid.org/0000-0003-4315-4096, Coombes, Brian K. and Wright, Gerard D.
2014.
Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance.
Nature
510
, pp. 503-506.
10.1038/nature13445
|
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: | Publication |
| Status: | Published |
| Schools: | Schools > Medicine |
| Publisher: | Nature Research |
| ISSN: | 0028-0836 |
| Date of Acceptance: | 7 May 2014 |
| Last Modified: | 01 Nov 2022 09:21 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/87626 |
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