Natural Enfumafungin Analogues from Hormonema carpetanum and Their Antifungal Activities.

Ibrexafungerp, an inhibitor of fungal ß-(1,3)-d-glucan 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 ß-(1,3)-d-glucan synthase, which may be useful for developing new antifungal agents.

Heterologous activation and metabolites identification of the pks7 gene cluster from Saccharopolyspora erythraea.

The microbial genome remains a huge treasure trove for the discovery of diverse natural products. Saccharopolyspora erythraea NRRL23338, the industry producer of erythromycin, has a dozen of biosynthetic gene clusters whose encoding products are unidentified. Heterologous expression of one of the polyketide clusters pks7 in Streptomyces albus B4 chassis resulted in the characterization of its function responsible for synthesizing both 6-methylsalicyclic acid and 6-ethylsalicyclic acid. Meanwhile, two new 6-ethylsalicyclic acid ester derivatives were isolated as shunt metabolites. Their structures were identified by comprehensive analysis of MS and NMR experiments. Putative functions of genes within the pks7 BGC were also discussed.

Anti-inflammatory Oleanane-Type Triterpenoids Produced by Nonomuraea sp. MYH522 through Microbial Transformation.

Eleven oleanane-type triterpenoids named soyasapogenols B1-B11 have been obtained unexpectedly from a marine actinomycete Nonomuraea sp. MYH522. Their structures have been determined by extensive analysis of spectroscopic experiments and X-ray crystallographic data. Soyasapogenols B1-B11 exhibit subtle differences in the positions and degrees of oxidation on an oleanane skeleton. The feeding experiment suggested that soyasapogenols might be derived from soyasaponin Bb through microbial-mediated conversion. The biotransformation pathways from soyasaponin Bb to five oleanane-type triterpenoids and six A-ring cleaved analogues were proposed. The assumed biotransformation involves an array of reactions including regio- and stereo-selective oxidation. These compounds alleviated the 5,6-dimethylxanthenone-4-acetic acid-induced inflammation in Raw264.7 cells via the stimulator of interferon genes/TBK1/NF-κB signaling pathway. The present work provided an efficient approach for rapid diversification of soyasaponins and for developing food supplements with potent anti-inflammatory effects.

Natural occurrence, bioactivity, and biosynthesis of triene-ansamycins.

Triene-ansamycins such as ansatrienins and cytotrienins are characterized by three conjugated double bond motifs within a 21-membered benzenoid ansamycins. Their structural diversity exists in the different substituents in the C-11 or C-13 side chain or in the 3-amino-5-hydroxy benzoic acid moiety. More complex derivatives have been reported with fused ring systems which may be produced via intramolecular cycloaddition between phenol and triene. The biosynthetic gene clusters and biosynthetic pathway of ansatrienins and cytotrienins have been characterized. Based on biosynthetic knowledge, a series of structural analogs has been prepared by genomic manipulation. Triene-ansamycins exhibit significant anticancer activity. The structure-activity relationships and biological targets have been investigated. This mini-review presents a comprehensive survey of triene-ansamycins, which covers natural occurrence, biological activity, biosynthesis, structural derivatization, structure-activity relationships, and biological targets from 1967 to 2022. Eighty triene-ansamycins have been reported.