Fighting antimicrobial resistance by reprogramming peptide antibiotics from the past

Society urgently needs new therapeutic strategies to tackle multi-drug resistant (MDR) bacterial infections. Current serious bacterial pathogens include Staphylococcus aureus – the most widespread pathogen of the ESKAPE panel; Enterococci – a pathogen with limited antibiotic solution and Clostridium difficile (C. Difficile) – a spore-forming anaerobe responsible for recurrent gut infections in the elderly population. These cause a broad range of severe infections in both the community and hospitals, including infections resistant to front-line antibiotics including methicillin, daptomycin and vancomycin. While approaches to MDR infections typically involve discovering new antibiotic classes, strategies rarely address the issues raised on antibiotics discovered in the past for whose applications are limited due to cell/ organ toxicity or off-target effects in the microbiota. In this proposal, we will build on our peptide and medicinal chemistry programs applied to 3 peptide antibiotics – Tyrocidine A, Gramicidin S and Ramoplanin – which are all toxic for human cells, potent against resistant Gram-positive and C. Difficile pathogens with minimal development of bacterial resistance. Over the past few years, we have developed three key resources – effective peptide synthesis, high throughput antimicrobial testing against ~10 clinical isolates and cell toxicity assays. Our goal is to divide and conquer MDR pathogens by building new tools and knowledge to answer three current challenges in antibiotic development. Challenge & Peptide 1. We have chosen Tyrocidine A to understand membrane specificity between blood cells and bacteria. Challenge & Peptide 2. We have chosen Ramoplanin to control the bacterial specificity in the microbiota. Challenge & Peptide 3. We have chosen Gramicidin S to be transformed into an orally available peptide due to its similarities with cyclosporine. All our projects are multidisciplinary: - Chemistry and Analysis (e.g. Solid-phase peptide synthesis, RP-HPLC and LCMS). - Biochemistry (e.g. Protein expression and enzymatic assays). - Microbiology (e.g. Antimicrobial, stability and mechanistic assays). - Cell biology component (e.g. Red-blood cell haemolysis).