Membrane-active antibiotics against multi-drug resistant Gram negative bacteria (2016-2019)

Antibiotic-resistant bacteria are a serious & growing threat to human health & national healthcare systems. Multi-drug resistant Gram-negative (MDR G-ve) strains of K. pneumonia, E. coli, A. baumannii & P. aeruginosa & recent ESBL & NDM-1 phenotypes are of grave concern. However, the bacterial membrane is a final frontier for new drugs. Compounds that target bacterial membranes or intrinsic membrane components, such as moenomycin & the recently reported teixobactin, possess extremely low or unmeasurable rates of resistance. Whilst there are thousands of research papers on antimicrobial peptides, almost all of these are active only against G+ve bacteria and have activity limited to topical application. We have examined a class of disulphide constrained beta-hairpin peptides (DC-BHPs) with broad-spectrum activity against MDR G-ve bacteria that can translocate across both cytoplasmic- & outer- bacterial membranes. We have developed a sophisticated design model that optimises peptide hydrophobicity, amphipathicity, hydrophobic moment and pKa, which was validated with a focused library of variants from the parent structure. This enabled us to produce new DC-BHPs with potent activity in vitro & IN VIVO against MDR G-ve bacteria, with minimal toxicity or haemolysis. We propose to expand this pioneering work to other DC-BHPs (from horseshoe crabs, scorpions & spiders) to derive new antibiotic candidates. This will be achieved using a combination of chemoinformatic design, modelling, innovative peptide synthesis for introduction of natural and non-natural amino acids, biochemical, and microbiological assays. We will then optimise & validate leads in vivo to a candidate antibiotic for Investigative New Drug enabling studies.