In silico identification of two peptides with antibacterial activity against multidrug-resistant Staphylococcus aureus

Linda B. Oyama, Hamza Olleik, Ana Carolina Nery Teixeira, Matheus M. Guidini, James A. Pickup, Brandon Yeo Pei Hui, Nicolas Vidal, Alan R. Cookson, Hannah Vallin, Toby Wilkinson, Denise M. S. Bazzolli, Jennifer Richards, Mandy Wootton, Ralf Mikut, Kai Hilpert, Marc Maresca, Josette Perrier, Matthias Hess, Hilario C. Mantovani, Narcis Fernandez-FuentesChristopher J. Creevey, Sharon A. Huws

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Here we report two antimicrobial peptides (AMPs), HG2 and HG4 identified from a rumen microbiome metagenomic dataset, with activity against multidrug-resistant (MDR) bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA) strains, a major hospital and community-acquired pathogen. We employed the classifier model design to analyse, visualise, and interpret AMP activities. This approach allowed in silico discrimination of promising lead AMP candidates for experimental evaluation. The lead AMPs, HG2 and HG4, are fast-acting and show anti-biofilm and anti-inflammatory activities in vitro and demonstrated little toxicity to human primary cell lines. The peptides were effective in vivo within a Galleria mellonella model of MRSA USA300 infection. In terms of mechanism of action, HG2 and HG4 appear to interact with the cytoplasmic membrane of target cells and may inhibit other cellular processes, whilst preferentially binding to bacterial lipids over human cell lipids. Therefore, these AMPs may offer additional therapeutic templates for MDR bacterial infections.
Original languageEnglish
Article number58
Number of pages14
Journalnpj Biofilms and Microbiomes
Issue number1
Early online date14 Jul 2022
Publication statusPublished - 01 Dec 2022


  • Adenosine Monophosphate/pharmacology
  • Animals
  • Anti-Bacterial Agents/pharmacology
  • Antimicrobial Cationic Peptides/pharmacology
  • Humans
  • Lipids/pharmacology
  • Methicillin-Resistant Staphylococcus aureus
  • Microbial Sensitivity Tests
  • Staphylococcal Infections/drug therapy
  • Staphylococcus aureus/metabolism


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