Exploring new natural products by utilizing untapped secondary metabolic pathways in actinomycetes

Actinomycetes have produced a variety of bioactive secondary metabolites; however, discovering new actinobacterial natural products using conventional approaches has become increasingly challenging. Meanwhile, genomic studies of actinomycetes have revealed that numerous secondary metabolite biosynthetic gene clusters (SM-BGCs) remain untapped. Thus, utilizing these secondary metabolic pathways is expected to facilitate the discovery of new actinomycetes-derived natural products. In this review, I primarily describe our research on the utilization of these untapped actinobacterial SM-BGCs and the discovery of new secondary metabolites. First, I introduce our studies on the activation of silent SM-BGCs through the co-cultivation of various actinomycetes with mycolic acid-containing bacteria (MACB), which led to the identification of 20 actinobacterial secondary metabolites, including 16 new compounds. In the latter part, I describe our recent findings on arsenic-related secondary metabolism, which has been overlooked in model actinomycetes, including the identification of a novel organoarsenic natural product, and the elucidation of its unique biosynthetic strategy, which is independent of S-adenosylmethionine (SAM)-dependent enzymes.