In the late 1980s and 90s, important progress was made in the discovery of the molecular basis for the overproduction of penicillin G thanks to R&D projects funded by antibiotic producing companies like DSM Gist-Brocades and Antibióticos S. A. With the onset of Genetic Engineering we pioneered technologies for the genetic modification of Penicillium chrysogenum, the penicillin producing fungus. The genes for the biosynthesis of the antibiotic were identified and sequenced, finding that they were grouped and amplified in tandem repeats of alarge genomic region. The number of copies of this region was shown to correlate with the productivity of the strains.
Similarly, based on studies carried out in collaboration with researchers in public R&D centers, we identified the genetic mutation responsible of the increase of the production of the current industrial strains of Penicillium chrysogenum with respect to the Penicillium notatum isolated by Alexander Fleming.
Because of the high production level reached during more than 50 years of classical mutagenesis and selection programs on the industrial penicillin-producing strains, the molecular biology approaches only delivered the understanding of some of the modifications suffered by the strains during the random mutagenesis processes, but also helped to focus the improvement strategies to increase the success rate, and facilitated additional criteria for the selection of the strains for industrial upscaling, maintaining with the overall approaches yearly production improvements between 2 and 5%.