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

Abstract

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.

Discovery of Lactomodulin, a Unique Microbiome-Derived Peptide That Exhibits Dual Anti-Inflammatory and Antimicrobial Activity against Multidrug-Resistant Pathogens

“…However, it is still not known whether lugdunin itself acts as an ion transporter. Another example of microbiome-derived peptides includes the identification of two peptides (HG2 and HG4) with potent anti-inflammatory and antimicrobial activity against MRSA infection in vitro and in a Galleria mellonella model [ 53 ]. HG2 and HG4 exhibited their activity by selectively binding to bacterial lipids, thus affecting membrane permeability and, in parallel, decreasing the concentration of ATP inside the cell [ 53 ].…”

Evaluation of the Efficiency of Random and Diblock Methacrylate-Based Amphiphilic Cationic Polymers against Major Bacterial Pathogens Associated with Cystic Fibrosis

“…Time-kill assay was performed as previously described [60,62]. Log-phase bacteria were incubated in wells of a 96 wells microplate at a final concentration of 10 6 cell/mL with either medium alone (growth control), or 150 µM cetyltrimethylammonium bromide (CTAB), or copolymer at 4× MIC.…”

“…Induction of bacterial resistance by copolymers was evaluated as previously described [60,62,64]. Briefly, bacterial cultures were continuously exposed to copolymers or conventional antibiotics over 45 consecutive days for M. abscessus and 30 consecutive days for P. aeruginosa and S. aureus, through repeated broth microdilution susceptibility testing and determination of MIC values.…”

Microbial derived antimicrobial peptides as potential therapeutics in atopic dermatitis

“…When they examined the likelihood of resistance development after exposure to sub-MIC levels of these peptides, they found that the AMPs did not generate resistant mutants for 20 days. Moreover, the MIC remained within a 1-2-fold increase compared with mupirocin, a marketed topical antibiotic that had a 32-fold MIC increase ( 126 ). Nevertheless, there are reports of the development of resistance to the antimicrobial activity of HDPs ( 127 , 128 ), so the possibility of resistance developing in SPBs cannot be excluded.…”