Towards The Next 80 Years of Penicillin Production
Penicillins and synthetic beta-lactam antibiotics have dramatically transformed health care and quality of life in the 80 years since Alexander Fleming’s discovery of Penicillium. Large-scale production of beta-lactam antibiotics is the result of sustained industrial strain improvement, representing numerous rounds of mutagenesis and selection. Penicillin titers and productivities have increased by at least three orders of magnitude in the past 60 years, representing an unprecedented success in industrial strain improvement.
Current industrial Penicillium strains are derived from a single natural isolate of P. chrysogenum obtained during WWII from an infected cantaloupe. Biochemical and genetic analysis of industrial strains led to the identification of several important mutations in high-producing strains, including amplification of penicillin biosynthesis genes. However, much of the molecular basis for improved productivity remains to be elucidated. A detailed understanding of the molecular biology of P. chrysogenum is not only relevant for natural penicillins, but by applying genetic engineering approaches, it has become possible to extend the range of fermentation products to include beta-lactam derivatives that could previously only be produced by chemical modification.
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To gain more insight into penicillin synthesis, researchers have recently sequenced the 32.19 Mbp genome of P. chrysogenum and identified numerous genes responsible for key steps in penicillin production (Genome sequencing and analysis of the filamentous fungus Penicillium chrysogenum. Nature Biotechnology, 28 September 2008). DNA microarrays were used to compare the transcriptomes of the sequenced strain and a penicillinG high-producing strain. Transcription of genes involved in biosynthesis of valine, cysteine and alpha-aminoadipic acid – precursors for penicillin biosynthesis – as well as of genes encoding microbody proteins, was increased in the high-producing strain. Some gene products were shown to directly control beta-lactam output. Many key cellular transport processes involving penicillins and intermediates still remain to be characterized at the molecular level. Genes predicted to encode transporters were strongly overrepresented among the genes transcriptionally upregulated under conditions that stimulate penicillinG production, illustrating potential for future genomics-driven metabolic engineering.
Access to the full range of genomics techniques will be invaluable for further innovation in antibiotics production. Despite the massive improvements already achieved in classical strain improvement, further improvement of penicillin production remains a distinct possibility.
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Tags: Antibiotics, Bacteria, Biology, Biotechnology, Genetics, Health, Medicine, Microbiology, Podcast, Science
