Capsimycin derivatives from Streptomyces sp. PH9007 as α‑glucosidase inhibitors and insights into their biosynthetic gene cluster

Abstract

The increasing number of individuals with diabetes mellitus (DM) highlights the need to develop new diabetes medications. Polycyclic tetramate macrolactams (PTMs), characterized by a macrocyclic lactam containing an integrated tetramic acid ring, constitute an expanding group of extensively dispersed natural compounds with diverse biological functions. In this study, two Streptomyces strains were isolated from the roots of the medicinal plant Sinomenium acutum . Using the Global Natural Products Social (GNPS) web platform, three PTMs, namely, capsimycin (4), capsimycin B (5), and capsimycin G (6), were extracted from Streptomyces sp. PH9007, which was isolated from Sinomenium acutum . Compounds 4 and 5 inhibited α-glucosidase, with 4 and 5 exhibiting IC 50 values of 484.6 ± 14.10 μM and 366.9 ± 12.85 μM, respectively. Compound 5 also exhibited antibacterial and antifungal activities, with MICs of 16 µg/mL against MRSA, Staphylococcus aureus ATCC 29213 and Candida albicans CMCC 98001. The results of fluorescence quenching, UV–visible spectroscopy, molecular docking and molecular dynamics simulations of 5 with α-glucosidase indicated that this compound binds better with α-glucosidase. Whole-genome sequencing of PH9007 revealed a 6, 339, 217 bp chromosome and two plasmids (83, 532 bp and 167, 087 bp) containing 25 biosynthetic gene clusters (BGCs), including one exhibiting 56% sequence similarity to the ikarugamycin BGC. Furthermore, bioinformatics analysis revealed that the ikarugamycin BGC is widely distributed in microorganisms. Overall, this study highlights that PTM-type compounds may serve as promising compounds for the further development of α-glucosidase inhibitors and lays the foundation for research on their biosynthesis.