Microbiomes are complex ecosystems with microbes mainly working symbiotically, but occasionally needing to compete with each other for survival. Competitive advantage may be shown in many forms, including the production of antimicrobials, therefore microbiomes may offer a wealth of novel antimicrobials for future therapeutic uses. Indeed, the plight of antimicrobial resistance (AMR) is one of, if not the most, challenging situation for the human population, with predicted deaths due to multi-drug resistant (MDR) bacterial infections predicted to reach over 10 million by 2050. In a report by Lord Jim O'Neill, six potential strategies, namely phage therapy, lysins, antibodies, probiotics, immune stimulation and antimicrobial peptides were discussed as strategies that should be focussed upon to combat the increasing threat of AMR. Antimicrobial peptides (AMPs) are promising drug candidates to target MDR bacteria due to their low cost, and quick action which means that the bacteria have less time to develop resistance. As such, in recent years we have devoted much research to the discovery and characterisation of novel AMPs from gastrointestinal tract microbiomes. We used both functional and sequence-based metagenomics coupled with use of bioinformatic tools to prospect for novel antimicrobial peptides in rumen and chicken caecal microbiomes. We identified 181 potentially novel AMPs from a rumen bacterial metagenome using functional metagenomics and a further 5 using sequence-based metagenomics. Similarly, we identified 111 putative AMPs from the chicken caecal microbiome. Five of the selected rumen AMPs (Lynronne-1, Lynronne-2, Lynronne-3, HG2 and HG4) were effective against numerous Gram-positive and Gram-negative clinical MDR bacteria pathogens including methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa strains. Two of the characterised lead chicken microbiome AMP candidates CHK_9 and CHK_103 also show potent activity against MRSA and Acinetobacter baumannii strains. No decrease in MRSA susceptibility was observed after 25 days of sub-lethal exposure to these AMPs. The AMPs bound preferentially to bacterial membrane lipids and induced membrane permeability leading to cytoplasmic leakage. They showed in vivo efficacy in Galleria mellonella and murine infection models. Topical administration of Lynronne-1 (10% w/v) to a mouse model of MRSA wound infection elicited a significant reduction in bacterial counts, which was comparable to treatment with 2% mupirocin ointment. Our findings indicate that gut microbiomes may provide viable alternative antimicrobials for future therapeutic application.
|Publication status||Published - Dec 2018|
|Event||Molecular Microbiology Ecology Group (MMEG) Meeting 2018 - Swansea University Institute of Life Science, Swansea, United Kingdom|
Duration: 17 Dec 2018 → 18 Dec 2018
|Conference||Molecular Microbiology Ecology Group (MMEG) Meeting 2018|
|Period||17/12/2018 → 18/12/2018|