Secondary metabolism by industrially improved Penicillium chrysogenum strains

Penicillium chrysogenum is the filamentous fungus employed for the industrial production of the antibiotic penicillin. Penicillins are still widely used but produced by high yielding β-lactam strains that resulted from an extensive classical strain improvement (CSI) program that lasted for almost seven decades. CSI involves harsh treatments such as UV radiation and muster gas exposure that causes mutations some of which are beneficial for β-lactam production. However, the impact of CSI on other secondary metabolite pathways remained unknown.
In this thesis, a comparative analysis of the P. chrysogenum mutants from the CSI program was conducted that involved genome sequencing, transcriptome and metabolite production. The data indicates that during CSI most secondary metabolite pathways have been silenced by mutation in favor of the β-lactams. Among others, this resulted in the elimination of a group of bioactive compounds sorbicillinoids. These are yellow pigments that exhibit antimicrobial, anti-HIV and anti-cancer activities. Using the genome sequencing data, a key mutation in a sorbicillinoid biosynthetic gene was restored in an industrial P. chrysogenum strain readily allowing high level production. This system can now be used to resolve the biosynthetic pathway for sorbicillinoids and design methods to produce high bioactive derivatives.