Devof a elopment new simulation-guided approach to design antimicrobial peptides with high selectivity towards individual bacterial species

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The goal of this project is to develop new molecular dynamics (MD) simulation based peptide-design methods and apply them to design and optimize novel antimicrobial peptides (AMPs) that target individual bacterial species with high selectivity. Developing new antibacterials to tackle rapidly rising antibiotic resistance is one of the most pressing and critical unmet health care needs. This is reflected by the UK's Antimicrobial Resistance Strategy, which is part of a BBSRC focus area. AMPs are extremely promising pharmacophores, but their chemical diversity, flexible nature, and prohibitive number of possible configurations, combined with the lack of suitable design and optimization tools has hindered their translation into the clinic. My group and I have been working on developing quantitatively accurate experimentally validated molecular simulation methods to design membrane-active peptide for over 15 years. This proposal builds on this expertise and will deliver new experimentally validated physical simulation methods for rational design and optimization of new AMPs. Current antibiotics are increasingly failing due to the emergence of drug-resistant bacterial strains. At the same time the pharmaceutical industry is retreating from the development of new antibiotics. This is because the extremely high cost of developing new antibiotics cannot be recuperated, as any new drugs will need to be held in reserve to treat drug-resistant infections. Hence there is not only a critical unmet need to develop new antibiotic therapies, but also a need for methods that bring down the cost of antibacterial pharmacophore design and validation. AMPs present one of the most promising classes of antimicrobial pharmacophores. They are more resilient than antibiotics against antimicrobial resistance formation, easy to produce and modify, and offer a near-infinite chemical and structural reservoir, which remains largely untapped. In our preliminary work (patent pending), we show that AMPs can be designed to provide a key feature desirable for next-generation antimicrobials: precise and exclusive targeting of specific pathogenic microbes without harming symbiotic bacteria or human tissues. Here we will build on this work to develop new simulation-guided methods to design AMPs that target specific bacterial species with high selectivity. First we apply unbiased atomic detail peptide partitioning MD simulations to design sequences that bind efficiently to specific membrane models of bacteria and human cells. Next we will combine genetic algorithms and molecular assembly simulations to introduce pore-forming mutations into these membrane-targeting sequences. These simulation approaches, developed by us, utilize sophisticated algorithms and methodologies that will allow us to iteratively simulate tens of thousands of sequence mutations to actively select for peptides that partition and form pores in specific membranes with high selectivity. These designed functional sequences will then serve as templates for experimental optimization using a combinatorial peptide library approach. This combined simulation-guided design and experimental optimization approach is equivalent to screening millions of peptide sequences, in a fraction of the cost and time. We will validate the functional characteristics and targeted antibacterial activity of the designed AMPs by in vitro screening against live bacteria and human cell lines.The methods developed here will not only provide urgently needed design tools to realize the potential of AMPs as pharmacophores, but also fundamentally advance our understanding of how specific peptide sequences target bilayers with particular lipid compositions, and shed new light on the molecular mechanisms driving the formation of peptide pores in cellular membranes.