Molecular insights on the biosynthesis of antitumour compounds by actinomycetes

Abstract

Natural products are traditionally the main source of drug leads. In particular, many antitumour compounds are either natural products or derived from them. However, the search for novel antitumour drugs active against untreatable tumours, with fewer side-effects or with enhanced therapeutic efficiency, is a priority goal in cancer chemotherapy. Microorganisms, particularly actinomycetes, are prolific producers of bioactive compounds, including antitumour drugs, produced as secondary metabolites. Structural genes involved in the biosynthesis of such compounds are normally clustered together with resistance and regulatory genes, which facilitates the isolation of the gene cluster. The characterization of these clusters has represented, during the last 25 years, a great source of genes for the generation of novel derivatives by using combinatorial biosynthesis approaches: gene inactivation, gene expression, heterologous expression of the clusters or mutasynthesis. In addition, these techniques have been also applied to improve the production yields of natural and novel antitumour compounds. In this review we focus on some representative antitumour compounds produced by actinomycetes covering the genetic approaches used to isolate and validate their biosynthesis gene clusters, which finally led to generating novel derivatives and to improving the production yields.

Figure 1

Structures of some polyketide and non‐ribosomal peptide antitumour compounds produced by actinomycetes.

Figure 2

Structures of some mixed polyketide/non‐ribosomal peptide, indolocarbazole and heterocyclic quinone antitumour compounds produced by actinomycetes.

Figure 3

Strategies used for generating novel antitumour derivatives and improving production yields by combinatorial biosynthesis.

Figure 4

Genetic organization of antitumour biosynthesis gene clusters summarized in Table 1.

Figure 5

A. Structures of novel antitumour derivatives generated by mutasynthesis or modification of the structural core.
B. Altered features and their comparison with the unmodified compound.

Figure 6

Structures of novel antitumour derivatives generated by tailoring modification showing the genes inactivated (crossed) or expressed for the generation of the novel compound.

Figure 7

Structures of novel antitumour derivatives with an altered glycosylation pattern by using plasmids directing the biosynthesis of different deoxysugars.