Journal Article

Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance

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

2014

Overview

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. A natural adjuvant for β-lactam antibiotics 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.

• Publisher: Nature Publishing Group UK
• Subject: 631/154/349 / Animals / Anti-Bacterial Agents - pharmacology / Aspartic Acid - analogs & derivatives / Aspartic Acid - isolation & purification / Aspartic Acid - pharmacology / Aspergillus - chemistry / beta-Lactam Resistance - drug effects / beta-Lactamase Inhibitors / beta-Lactamases - genetics / beta-Lactamases - metabolism / Biological Products - isolation & purification / Biological Products - pharmacology / Carbapenems - pharmacology / Drug Evaluation, Preclinical / Drug Synergism / Female / Gram-Negative Bacteria - drug effects / Gram-Negative Bacteria - enzymology / Gram-Negative Bacteria - genetics / Humanities and Social Sciences / Klebsiella pneumoniae - drug effects / Klebsiella pneumoniae - enzymology / Klebsiella pneumoniae - genetics / Meropenem / Mice / multidisciplinary / Science / Thienamycins - pharmacology