Aspergillomarasmine A overcomes metallo-beta-lactamase antibiotic resistance

作者：King, Andrew M.; Reid-Yu, Sarah A.; Wang, Wenliang; King, Dustin T.; De Pascale, Gianfranco; Strynadka, Natalie C.; Walsh, Timothy R.; Coombes, Brian K.; Wright, Gerard D.^*

来源：Nature, 2014, 510(7506): 503-+.

DOI：10.1038/nature13445

• ANGIOTENSIN-CONVERTING ENZYME
• KLEBSIELLA-PNEUMONIAE
• MICROBIAL INHIBITORS

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.

• 出版日期2014-6-26