Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance

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. The emergence of Gram-negative pathogens resistant to carbapenem antibiotics is a global health concern and carbapenem resistance often arises through acquisition of β-lactamase enzymes; this study identifies the natural fungal product aspergillomarasmine A as a metallo-β-lactamase inhibitor and a potential treatment to tackle carbapenem resistance. Infection with Gram-negative pathogens bearing metallo-β-lactamases such as NDM-1 and VIM is a growing public health problem and threatens the use of penicillin, cephalosporin and carbapenem antibiotics to treat infections. Here, Gerard Wright and colleagues report a screen for naturally produced inhibitors of NDM-1 in an extensive collection of DMSO-dissolved natural product extracts derived from environmental microorganisms. One extract (from Aspergillus versicolor) exhibited a particularly potent anti-NDM-1 activity and was identified as aspergillomarasmine A (AMA), a natural product first reported some 50 years ago associated with leaf wilting. AMA is a rapid and potent inhibitor of both NDM-1 and VIM-2, and the authors find that AMA fully restores antibiotic efficacy in vitro and in vivo against bacterial pathogens possessing either VIM- or NDM-type resistance genes. AMA is non-toxic and well tolerated, making it a realistic prospect as an antibiotic adjuvant.