Fengycins are a family of cyclic lipo-depsipeptides produced by Bacillus spp. They display potent antifungal properties and they are used as biocontrol agents in agriculture (SerenadeTM). Fengycins, similar to other lipopeptides, cause permeabilization of cell membranes leading to cell leakage and disruption of the ion gradient. To date no systematic study has been conducted on the Fengycins to determine the functional relevance of either the amino-acids present or the lipidated tail.
This lack of structure-function data is largely due to the highly labile depsi-bridge found within the Fengycin structure, which is hydrolysed even under the mildest conditions. The poor stability of this ester bridge has meant that to date no total chemical SPPS strategy has succeeded in delivering a complete natural Fengycin peptide. Moreover, only very recently, a SPPS approach has been reported which enables the synthesis of several Fengycin analogues. While a step forward in the field, the reported approach only afforded modest product yields (10-35%) and it did not address the challenge of the Fengycin’s innate instability issues.
In order to address the challenges of both synthesis and stability, we have designed a new class of Fengycin analogues with enhanced chemical stabilities enabled through replacement of the natural ester depsi-bridge by an amide-bridge. We have also developed a novel SPPS route that allows the total synthesis of Fengycin analogues on resin, in high yields and high crude peptide purity (e.g. 60-80%). In addition, we have tested our analogues against Rhizopus stolonifer and Pseudomonas aeruginosa. Our initial studies confirmed biological activity for most of the novel amide-bridged analogues, and they give new insight into the structural activity relationships of Fengycin peptides (e.g. expensive D-Allo-Thr not needed, lipid tail can be simplified). Our results open up new opportunities for Fengycin structural optimization and future commercial applications.