Myxadazoles, Myxobacterium‐Derived Isoxazole–Benzimidazole Hybrids with Cardiovascular Activities

Abstract

There is a continuous need for novel microbial natural products to fill the drying‐up drug development pipeline. Herein, we report myxadazoles from Myxococcus sp. SDU36, a family of novel chimeric small molecules that consist of N‐ribityl 5,6‐dimethylbenzimidazole and a linear fatty acid chain endowed with an isoxazole ring. The experiments of genome sequencing, gene insertion mutation, isotope labelling, and precursor feeding demonstrated that the fatty acid chain was encoded by a non‐canonical PKS/NRPS gene cluster, whereas the origin of N‐ribityl 5,6‐dimethylbenzimidazole was related to the vitamin B12 metabolism. The convergence of these two distinct biosynthetic pathways through a C‐N coupling led to the unique chemical framework of myxadazoles, which is an unprecedented hybridization mode in the paradigm of natural products. Myxadazoles exhibited potent vasculogenesis promotion effect and moderate antithrombotic activity, underscoring their potential usage for the treatment of cardiovascular diseases.

Predatory Activity of Myxobacteria Corallococcus exiguus against Soil Inhabiting Bacteria

“…They are able to form fruiting bodies when starving, move on a solid surface, and produce chemical compounds capable of killing their prey microorganisms. Some of the recently found chemical compunds from myxobacteria are myxadazoles (Li et al, 2021) and myxochelins (Wang et al, 2021). With the increasing need for the new antibiotics due to antimicrobial resistance, exploring predatory microorganisms as a source of novel antibiotics has become an alternative endeavor to tackle this problem.…”

Discovery and biosynthesis of specialized metabolites produced by an indigenous streptomyces strain

“…A small number of so-called hybrid natural products have been reported to be produced by merging biosynthetic pathways via a late-stage enzymatic or non-enzymatic reaction. [398][399][400][401][402][403][404] However, the formation of hybrid natural products via the aryl diazonium-mediated Japp-Klingemann reaction is unprecedented, which expands the repertoire of the chemical reactions known to be involved in natural product biosynthesis.…”