Bacterial natural products: Prediction, regulation and characterization of biosynthetic gene clusters in Actinobacteria

Secondary metabolites are produced by many microbes. They are not essential for life, but may provide a competitive advantage in the natural environment. Antibiotics are an important example, crucial agents in the human health system, widely used to combat infectious diseases. In view of the emergence of (multi)antibiotic resistant pathogenic bacteria in recent years, there is an urgent need to discover new and effective antibiotics. Improvements in DNA sequencing techniques, and bioinformatics tools to analyze genome sequences, showed that microorganisms potentially can produce many more compounds than initially thought. Most of these compounds are not produced under laboratory conditions (cryptic biosynthetic gene clusters). This PhD thesis analyzed different strategies to identify and produce new secondary metabolites (antibiotics). Focus was on the genus Streptomyces, producing most of the antibiotics currently used in medicine, and on the genus Rhodococcus, which had hardly been studied. Synthesis of the blue pigment indigoidine and the tunicamycin-like antibiotics from Streptomyces clavuligerus ATCC 27064 was analyzed in detail. This thesis also reports an analysis of the genome sequences of 20 different Rhodococcus strains, revealing an impressive diversity of (novel) secondary metabolite gene clusters. Remarkably, the -butyrolactone signalling system, known to control antibiotic synthesis in various Streptomyces strains, was also present in Rhodococcus jostii RHA1, and characterized. This system thus may allow inter-generic communication to occur. This thesis therefore gives important insights in the (regulation of) secondary metabolism in S. clavuligerus ATCC 27064 and members of the Rhodococcus genus.