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Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance

Andrew M King1, Sarah A Reid-Yu2, Wenliang Wang3

  • 11] M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada [2] Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4K1, Canada.

Nature
|June 27, 2014
PubMed

Insights

A new fungal compound, aspergillomarasmine A (AMA), effectively inhibits metallo-β-lactamases (MBLs). AMA restores carbapenem antibiotic effectiveness against resistant Gram-negative pathogens, offering a potential new treatment.

Area of Science:

  • Microbiology
  • Infectious Diseases
  • Drug Discovery

Background:

  • Carbapenem-resistant Gram-negative pathogens pose a significant global health threat.
  • Metallo-β-lactamases (MBLs), like NDM-1, are key enzymes conferring resistance to critical antibiotics.
  • Existing treatments are limited due to widespread resistance.

Purpose of the Study:

  • To identify novel inhibitors of MBL enzymes.
  • To evaluate the potential of these inhibitors to restore antibiotic activity against resistant bacteria.
  • To assess therapeutic efficacy in a preclinical model.

Main Methods:

  • Screening of fungal natural products for MBL inhibitory activity.
  • Biochemical assays to determine enzyme inhibition potency.
  • In vitro testing of antibiotic re-sensitization in resistant Gram-negative bacteria.
  • In vivo efficacy studies in a mouse infection model.

Main Results:

  • Aspergillomarasmine A (AMA) was identified as a potent inhibitor of NDM-1 and VIM-2 MBLs.
  • AMA restored meropenem activity against various Gram-negative pathogens, including Enterobacteriaceae, Acinetobacter spp., and Pseudomonas spp.
  • Combination therapy with AMA and meropenem demonstrated therapeutic potential in a mouse model of Klebsiella pneumoniae infection.

Conclusions:

  • Aspergillomarasmine A is a promising MBL inhibitor with the potential to combat carbapenem resistance.
  • AMA can re-sensitize resistant Gram-negative pathogens to carbapenems.
  • Combination therapy of AMA and carbapenems offers a viable strategy to treat infections caused by MBL-producing bacteria.

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