Rare actinomycetes are biosynthetically ‘talented’ microorganisms and have the ability to produce novel bioactive secondary metabolites (Ding et al., 2019; Wei et al., 2023). Our recent study suggests that some rare genera of actinomycetes, such as Kutzneria, Kibdelosporangium, Saccharothrix, Cystobacter, Actinosynnema, and Kitasatospora, demonstrated a significant, yet underexplored, biosynthetic potential that is not less than that of Streptomyces, but these genera have received much less attention overall (Wei et al., 2021). A systematic review and analysis of the secondary metabolites and biosynthetic potential of rare genera of actinomycetes will facilitate the efficient discovery of novel secondary metabolites from these sources.

Saccharothrix is a genus of Actinomycetales that was originally identified by Labeda et al. in 1984 (Labeda et al., 1984), and has been known to produce many structurally diverse secondary metabolites, such as karnamicins (4-(pyridin-2-yl)thiazole), saccharomicins (heptadecaglycoside), tianchimycins (16-membered macrolides), saccharothriolides (10-membered macrolides), saccharothrixones (angucyclinones), and saccharochelins (tetrapeptides) (Nishio et al., 1989; Kong et al., 1998; Wang et al., 2013; Lu et al., 2015; Gan et al., 2015; Shen et al., 2021b). Some of the metabolites have shown excellent antibacterial, antifungal, or antitumour activities; for example, ammocidin, a 20-membered glycosylated macrolactone isolated from the culture broth of Saccharothrix sp. AJ9571, can induce apoptotic cell death in Ras-dependent Ba/F3-V12 cells with an IC50 of 66 ng/mL (Murakami et al., 2001b). However, biosynthetic pathways and corresponding biosynthetic gene clusters (BGCs) have been identified for very few secondary metabolites isolated from Saccharothrix (Shen et al., 2021a; Zhu et al., 2017; Mo et al., 2017b; Gummerlich et al., 2020; Shen et al., 2021b; Saugar et al., 2017; Felnagle et al., 2007; Zhao et al., 2021; Huang et al., 2015; Sánchez et al., 2002; Yu et al., 2023; Gorniaková et al., 2021). Our recent study showed that the genome of species in this genus encodes an average of 36 BGCs (Wei et al., 2021), implying that the majority of BGCs have not been linked to the reported secondary metabolites or have not been excavated. Systematic analysis of the corresponding relationship between the reported secondary metabolites and the encoding BGCs in Saccharothrix will help uncover the secondary metabolic potential of this genus and help guide the directional excavation of novel secondary metabolites from this genus. However, the biosynthetic potential of Saccharothrix and secondary metabolites isolated from the genus have not been previously explored or reviewed.

In this comprehensive review, the chemical structures and bioactivities of all the reported secondary metabolites isolated from Saccharothrix are discussed in terms of their biosynthetic mechanisms. The identified BGCs and biosynthetic pathways of metabolites from Saccharothrix are highlighted, and the BGCs are compared with the BGCs predicted from all available high-quality genomes of Saccharothrix and BGCs collected from the MIBiG database (Terlouw et al., 2023). Then, we linked the secondary metabolite families to the biosynthetic gene cluster families (GCFs) through cheminformatic and bioinformatic approaches; this review reveals the underexplored biosynthetic potential of Saccharothrix and provides much valuable information for the targeted discovery and biosynthesis of natural products from this genus.