Regulation of antibiotic production in Streptomyces coelicolor. A bacterial hormone receptor variant and the awakening of a cryptic antibiotic biosynthesis gene cluster

PhD ceremony: Mr. M. Gottelt, 14,45 uur, Academiegebouw, Broerstraat 5, Groningen

Thesis: Regulation of antibiotic production in Streptomyces coelicolor. A bacterial hormone receptor variant and the awakening of a cryptic antibiotic biosynthesis gene cluster

Promotor(s): prof. L. Dijkhuizen

Faculty: Mathematics and Natural Sciences

The number of genuinely new antibiotics available has been declining for decades while development of drug resistance among pathogenic bacteria advances. Therefore, the search for pharmaceutically active compounds has moved back into the centre of scientific interest.

More than three quarters of the clinically used antibiotics are natural products deriving mostly from fungi and certain soil bacteria, the streptomycetes. Antibiotic production is strictly regulated, and in Streptomyces coelicolor it is controlled by ‘bacterial hormones’. The small signalling molecules allow communication between the millions of cells forming a S. coelicolor colony and trigger the synchronised onset of antibiotic production in all cells.

Using molecular biological techniques, Marco Gottelt manipulated this regulatory system, which promptly led to the production of a novel antibiotic: Deletion of the regulatory protein ScbR2 resulted in the production of a hitherto unseen yellow pigment (yCPK) and a so-far unknown antibiotic (abCPK). The new antibiotic has activity against a broad range of potentially harmful bacteria. The deletion of the regulator ScbR2 activated a whole group of genes, the cpk gene cluster. This gene cluster was shown to be required for the synthesis of yCPK and abCPK. After optimisation of the growth conditions, the mutant produced the abCPK antibiotic in amounts sufficient for further characterisation of the compound.

Similar regulatory systems and numerous inactive antibiotic gene clusters are present in most antibiotic producing organisms. Gottelt’s work shows that by manipulating such a regulatory system one can awaken these sleeping genes. According approaches are possible in other bacteria and this will possibly lead to the discovery of many more novel antibiotics with the potential to be developed into drugs to combat resistant pathogens.