Fengycin A Analogues with Enhanced Chemical Stability and Antifungal Properties

Abstract

Fengycins are cyclic lipo-depsipeptides produced by Bacillus spp. that display potent antifungal properties but are chemically unstable. This instability has meant that no total synthesis of any fengycin has been published. Here we report the synthesis of fengycin A analogues that display enhanced antifungal properties and chemical stability under both basic and acidic conditions. The analogues prepared also demonstrate that the fengycin core structure can be modified and simplified without the loss of antifungal activity.

Figure 1

(A) General structure of fengycin. (B) Proposed approach for fengycin stabilization.

Figure 2

(A) Synthesis of cyclic peptidyl-resin 6. LC/(ESI⁺)MS traces of cleaved sample aliquots of 5 before (B) and after cyclization (C) showing quantitative conversion to the cyclic product 6 (λ= 254 nm).

Figure 3

(A) Chemical synthesis of Trt-l-4(NFmoc)Aph-OH (9). (B) Complete total SPPS strategy, based on a quaternary Fmoc/Trt/Dmab/(tBu/Boc) protection scheme, developed in this study for the preparation of lactam fengycin analogues 17A–D. Product purities of the crude materials are given as analyzed by RP-HPLC (λ= 220 nm). (C) HPLC traces of crude peptides 17A–D (λ= 220 nm).

Figure 4

Effect of natural and synthetic fengycins on the growth of Fusarium graminearum. Fungal growth was measured in the absence (control) or presence of 500 μg/mL fengycin. t tests confirmed that all differences between natural and synthetic fengycins were significant (p < 0.05).