Synthesis and structural studies of macrocyclic antimicrobial peptides

Unfortunately, most clinically approved antimicrobials have been on the market for decades and therefore have at least one, if not multiple, known resistance mechanisms. Antimicrobial peptides (AMPs), naturally occurring molecules with diverse structures and modifiable backbones, offer a promising source of new antibiotics.

This research focuses on two cyclic lipopeptides (CLiPs), globomycin and brevicidine, both active against Gram-negative bacteria. <br>Previous synthetic methods for globomycin relied on solution-phase or fragment-based strategies, this study explored an on-resin approach using side-chain immobilisation to streamline synthesis. Despite extensive condition screening, a fully on-resin method was ultimately unfeasible. However, the project led to the successful development of a stereoselective strategy for synthesising complex disubstituted lipids via cross-metathesis, providing a flexible synthetic template for producing diverse lipid building blocks useful throughout natural product synthesis.<br><br>To improve globomycin’s stability, a library of twelve analogues was created by replacing its hydrolysis-prone ester linkage with amide and olefin bonds.