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.

Beyond Soil-Dwelling Actinobacteria: Fantastic Antibiotics and Where to Find Them

“…The trend to combine different classes of biochemical pathways to generate chemical diversity seems to be general among this group of bacteria, as illustrated by leupyrrins ( Figure 10 ), which combine within their structures moieties originated by PKS, NRPS and terpene biosynthetic machineries [ 212 , 213 ]. The potentially antithrombotic myxadazoles ( Figure 10 ) are unprecedented hybrid compounds, combining a benzimidazole moiety (derived from vitamin B12 metabolism) with a linear fatty acid (of PKS-NRPS origin) endowed with an isoxazole ring [ 214 ]. Remarkably, the NRPS and PKS assembly lines found in myxobacteria often diverge from the canonical models found in other bacteria in terms of module architectures, biochemical behavior, building block selection and chain termination [ 215 ].…”

Classifying Natural Products from Plants, Fungi or Bacteria using the COCONUT Database and Machine Learning

“…In details, the fungal epicospirocin 1 [33], penicimeroterpenoid A [34], beetleane A [35], funiculolide D [36], and fusoxypenes A [37], the bacterial vertirhodin A [38], bosamycin A [39], and dumulmycin [40], and the plant fortuneicyclidin A [41], meloyunnanine A [42], hyperfol B [43], pegaharmol A [44], hunzeylanine A [45], mucroniferal A [46], perovsfolin A [47], horienoid A [48], and erythrivarine J [49] were correctly classified. On the other hand, the fungal rhizolutin [50] and myxadazoles A [51] and the bacterial marinoterpin A [52] were misclassified. Note that in these cases, the percentage values to the assigned class were lower than for the correct predictions.…”

Classifying Natural Products from Plants, Fungi or Bacteria using the COCONUT Database and Machine Learning

“…On the other hand, the fungal rhizolutin [50] and myxadazoles A [51] and the bacterial marinoterpin A [52] were misclassified. Note that in these cases, the percentage values to the assigned class were lower than for the correct predictions.…”