Natural Enfumafungin Analogues from Hormonema carpetanum and Their Antifungal Activities

Abstract

Ibrexafungerp, an inhibitor of fungal β-(1,3)-Dglucan synthase, represents the first new class of antifungals to be approved in the last 20 years. Ibrexafungerp is a semisynthetic derivative of the naturally occurring triterpene glycoside enfumafungin. In order to search for new analogues of enfumafungin and to probe its biosynthesis, we undertook a reinvestigation of Hormonema carpetanum, which led to the isolation of two new analogues, enfumafungins B and C, together with enfumafungin. Due to the presence of a hemiacetal moiety in the structure, the enfumafungins appear as a mixture of two interconverting epimers during both the purification process and NMR data acquisition. The structure elucidation, including the differentiation of 25S* and 25R* epimers, was completed by combined analyses of NMR and MS spectroscopic data. The discovery of enfumafungins B and C may have implications for enfumafungin biosynthesis. The antifungal activity of enfumafungins B and C was significantly lower than that of enfumafungin, suggesting that the C-2 substituents and the C-19 carboxy acid are important for activity. Molecular docking simulations revealed significant hydrogen bond interactions between enfumafungins and β-(1,3)-D-glucan synthase, which may be useful for developing new antifungal agents.

Biosynthesis of Enfumafungin-type Antibiotic Reveals an Unusual Enzymatic Fusion Pattern and Unprecedented C–C Bond Cleavage

“…niger R330 (Table S4). Further analysis of the structure–activity relationship revealed that the cleaved E-ring was essential for the antifungal activity, as observed in the comparison between compounds 1 and 12 , as well as between compounds 8 and 4 , which aligns with previous findings . Moreover, compound 8 demonstrated higher potency than compound 11 , suggesting that C3β- d -glucopyranose plays a critical role in its activity.…”

“…Further analysis of the structure−activity relationship revealed that the cleaved E-ring was essential for the antifungal activity, as observed in the comparison between compounds 1 and 12, as well as between compounds 8 and 4, which aligns with previous findings. 46 Moreover, compound 8 demonstrated higher potency than compound 11, suggesting that C3β-D-glucopyranose plays a critical role in its activity. Therefore, both the E-ring cleavage enzyme FsoE and chimeric enzyme FsoA hold the potential for the transformation of biologically active enfumafungin-type antibiotics.…”

Current Perspectives of Antifungal Therapy: A Special Focus on <em>Candida auris</em>

“…Enfumafungin analogues were isolated; they are enfumafungin B and C. Both compounds were effective against clinically relevant C. auris with the MIC of 64 µg/mL. Further molecular docking studies confirmed that these compounds binded in transmembrane region of FKS1 of β-(1,3)-D-glucansynthase [63].…”

Current Perspectives of Antifungal Therapy: A Special Focus on Candida auris

“…Both compounds were effective against clinically relevant C. auris with a MIC of 64 µg/mL. Further molecular docking studies confirmed that these compounds bonded in the transmembrane region of FKS1 of β-(1,3)-D-glucansynthase [ 64 ].…”