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.
33 Herein we report the identification and characterisation of two linear antimicrobial peptides 34 (AMPs), HG2 and HG4, with activity against a wide range of multidrug resistant (MDR) 35 bacteria, especially methicillin resistant Staphylococcus aureus (MRSA) strains, a highly 36 problematic group of Gram-positive bacteria in the hospital and community environment. To 37 identify the novel AMPs presented here, we employed the classifier model design, a feature 38 extraction method using molecular descriptors for amino acids for the analysis, visualization, 39 and interpretation of AMP activities from a rumen metagenomic dataset. This allowed for the in 40 silico discrimination of active and inactive peptides in order to define a small number of 41 promising novel lead AMP test candidates for chemical synthesis and experimental evaluation. In 42 vitro data suggest that the chosen AMPs are fast acting, show strong biofilm inhibition and 43 dispersal activity and are efficacious in an in vivo model of MRSA USA300 infection, whilst 44 showing little toxicity to human erythrocytes and human primary cell lines ex vivo.45 Observations from biophysical AMP-lipid-interactions and electron microscopy suggest that 46 the newly identified peptides interact with the cell membrane and may be involved in the 47 inhibition of other cellular processes. Amphiphilic conformations associated with membrane 48 disruption are also observed in 3D molecular modelling of the peptides. HG2 and HG4 both 49 preferentially bind to MRSA total lipids rather than with human cell lipids indicating that HG4 50 may form superior templates for safer therapeutic candidates for MDR bacterial infections. 52Author Summary 53 We are losing our ability to treat multidrug resistant (MDR) bacteria, otherwise known as 54 superbugs. This poses a serious global threat to human health as bacteria are increasingly 55 acquiring resistance to antibiotics. There is therefore urgent need to intensify our efforts to 56 develop new safer alternative drug candidates. We emphasise the usefulness of complementing 57 wet-lab and in silico techniques for the rapid identification of new drug candidates from 58 environmental samples, especially antimicrobial peptides (AMPs). HG2 and HG4, the AMPs 59 identified in our study show promise as effective therapies for the treatment of methicillin 3 60 resistant Staphylococcus aureus infections both in vitro and in vivo whilst having little 61 cytotoxicity against human primary cells, a step forward in the fight against MDR infections. 4 62 63 The decline in effective treatment strategies for multidrug resistant (MDR) bacterial infections 64 due to the problem of antibacterial resistance threatens our ability to treat infections now and 65 in the future, and calls for an urgent need to explore new safe drug candidates and alternative 66 treatment strategies 1 . The MDR Gram positive bacteria, methicillin resistant Staphylococcus 67 aureus (MRSA), a human opportunistic pathogen, has become a leading causative agent of 68 hospita...
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