Chemistry and biology of specialized metabolites produced by Actinomadura

Abstract

Covering: up to the end of 2022In recent years rare Actinobacteria have become increasingly recognised as a rich source of novel bioactive metabolites. Actinomadura are Gram-positive bacteria that occupy a wide range of ecological niches. This review highlights about 230 secondary metabolites produced by Actinomadura spp., reported until the end of 2022, including their bioactivities and selected biosynthetic pathways. Notably, the bioactive compounds produced by Actinomadura spp. demonstrate a wide range of activities, including antimicrobial, antitumor and anticoccidial effects, highlighting their potential in various fields.

Fig. 1. Structures of polyethers produced by Actinomadura.

Fig. 2. Proposed biosynthetic pathway for tetramadurin, a 31-carbon polyketide skeleton, by the mad gene cluster in A. verrucosopora, based on the bioinformatics analysis and functional analysis of gene deletions.

Fig. 3. Structure of spirotetronate polyketides.

Fig. 4. Biosynthetic pathway for the kijanimicin aglycone core, involving PKS genes, glycerol-derived three-carbon units, and intramolecular cyclizations, leading to formation of the octahydronaphthalene and spirotetronate rings. Two different sugar biosynthetic pathways bifurcate from intermediate TDP-2,6-dideoxy-3,4-diketo-d-glucose (41).

Fig. 5. Structure of fluvirucins.

Fig. 6. Modular type I PKS gene clusters of fluvirucins B1 and B2 from A. vulgaris and A. fluva subsp. indica, respectively. Feeding experiment shows incorporation of labelled l-aspartic acid and biochemical studies propose a pathway for the generation and loading of β-alanine, a unique component of the macrolactam structure.

Fig. 7. Structure of maduropeptin, maduropeptin-methanol adduct and esperamicins enediynes.

Fig. 8. Mechanism of action of enediynes in antitumor and antibacterial activity through Bergman cyclization and DNA cleavage.

Fig. 9. The biosynthetic pathway of maduropeptin chromophore involves the iterative type I PKS MdpE and several tailoring enzymes. These enzymes facilitate modifications, including the addition of an amino sugar, 3,6-dimethylsalicylyl-CoA, and (S)-3-(2-chloro-3-hydroxy-4-methoxyphenyl)-3-hydroxypropionic acid, which are attached to the enediyne core intermediate.

Fig. 10. Structures of pradimicins.

Fig. 11. The biosynthesis of pradimicins is directed by the pdm gene cluster, with PdmABC acting as the minimal type II polyketide synthase enzymes. Modifications by ligases, P₄₅₀ enzymes, methyltransferases, and glycosyltransferases lead to the final molecule.

Fig. 12. Structure of angucyclinones.

Fig. 13. Structure of anthrones.

Fig. 14. Structure of anthracyclines, DNA targeting compounds produced by Actinomadura.

Fig. 15. Structure of rubterolones, maduralactomycins and actinospirols.

Fig. 16. Proposed biosynthetic pathway for rubterolones involving a cascade of enzymes and nonenzymatic spontaneous pyridine ring formation from prerubterolones A–C (138–140).

Fig. 17. Xanthones from Actinomadura.

Fig. 18. Other polyketides isolated from culture extract of Actinomadura.

Fig. 19. Structure of madurastatins isolated from Actinomadura strains.

Fig. 20. Biosynthesis of (−)-madurastatin C1 by the NRPS mad gene cluster from Actinomadura strain WMMA-1423. The cluster includes enzymes for salicylate synthesis. Homologous enzymes from the rene gene cluster are also shown.

Fig. 21. Structure of GE23077 A and B and GE23077 linked to rifamycin SV (195).

Fig. 22. Structure of natalenamides.

Fig. 23. Structure of matlystatins.

Fig. 24. (a) Biosynthesis of matlystatins by a hybrid NRPS-PKS gene cluster. The unique decarboxylase–dehydrogenase MatG generates an electrophilic intermediate for the formation of carbon–sulfur or carbon–nitrogen bond in the final products. (b) Compounds produced by feeding different nucleophiles to culture medium.

Fig. 25. Structure of forazolines and incorporation of labelled propionate, acetate and l-cysteine into the structure of forazoline A.

Fig. 26. Structure of verucopeptin and thiazohalostatin.

Fig. 27. Miscellaneous metabolites produced by Actinomadura.

Fig. 28. Structure of indolocarbazoles from Actinomadura strains and pegcantratinib (250) drug generated based on SF-2370 (K-252a).

Fig. 29. Proposed biosynthetic assembly of indolocarbazoles. Biosynthesis of two groups of indolocarbazoles bifurcate from intermediate 259. Substitution of RebC with StaC can switch the downstream products.

Yousef Dashti

Jeff Errington