Aspergillomarasmine A overcomes metallo-b-lactamase antibiotic resistance

The emergence and spread of carbapenem-resistant Gram-negative pathogens is a global public health problem. The
acquisition of metallo-b-lactamases (MBLs) such as NDM-1 is a principle contributor to the emergence of carbapenemresistant
Gram-negative pathogens that threatens the use of penicillin, cephalosporin and carbapenemantibiotics 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 restoredthe activity ofmeropenemagainst Enterobacteriaceae, Acinetobacter spp. andPseudomonas spp. possessing
eitherVIMorNDM-type alleles. Inmice infectedwithNDM-1-expressing Klebsiella pneumoniae,AMAefficiently restored
meropenemactivity, 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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