NEW YORK (GenomeWeb News) – Netherlands-based life sciences and materials sciences company Royal DSM and collaborators from seven international research groups have sequenced the genome of the penicillin-producing fungus Penicillium chrysogenum, DSM announced yesterday.
Because P. chrysogenum is used for the industrial production of penicillin, the results are expected to have implications for the improving antibiotic production methods. The team also used microarrays to compare the transcriptomes of the strain that was sequenced with another “high-producing” penicillin strain to find genes that are ramped up or down in conjunction with penicillin production. The work appeared online this weekend in Nature Biotechnology.
“Never before has the sequence of this strain been mapped to this level or such important knowledge extracted,” lead author Marco van den Berg, a principal scientist in the Metabolic Engineering and Screening branch at DSM Anti-Infectives, said in a statement. “It is an absolute leap forward in the field of these antibiotics and it will generate many innovative development opportunities for both classical and new products.”
Penicillin was discovered by Sir Alexander Fleming some 80 years ago from the fungus Penicillium notatum, now known as P. chrysogenum. It produces several beta-lactam type antibiotics, including penicillin and related compounds. With time, systematic improvements in Penicillium strains by mutagenesis and selection have led to the large-scale production methods for beta-lactam antibiotics, the authors noted. But current strains are all believed to be derived from one natural strain isolated from cantaloupe during World War II.
“A detailed understanding of the molecular biology of P. chrysogenum is not only relevant for ‘classical’ penicillins,” van den Berg and his colleagues wrote. “By applying genetic engineering approaches, it has become possible to extend the range of fermentation products to include [beta]-lactam derivatives that could hitherto only be produced by chemical modification leading to great potential in terms of economy and sustainability.”
For the latest project, which started about four years ago, the researchers sequenced the 32.19 megabase P. chrysogenum Wisconsin54-1255 genome to nearly ten times coverage using whole-genome random sequencing. They also sequenced the 31,790 base-pair mitochondrial genome. They found that the P. chrysogenum genome contains 13,653 different genes, while the mitochondrial genome contains 17 open reading frames.
Based on their subsequent analysis, the researchers estimated that more than half — nearly 57 percent — of the P. chrysogenum genome is compromised of protein-coding sequences. Of these, 5,329 could be assigned to functional protein classes designating proteins involved in metabolism, energy, cellular transport, and protein fate.
A phylogenetic analysis suggested that P. chrysogenum was closely related to Aspergillus species (including Aspergillus niger, a species whose genome was sequenced by DSM last year), but distantly related to two other Penicillium species, P. marneffei and P. stipitatum. The researchers also pinpointed P. chrysogenum-specific genes.
In addition, their microarray analysis of the Wisconsin54-1255 strain and a high-producing strain called DS17690 suggests that more than 300 genes are up-regulated in the high-producing strain — including genes coding for enzymes producing penicillin precursors and dozens of genes coding for microbody proteins, while another 271 are down-regulated.
“Despite the massive improvements already achieved in classical strain improvement, our results indicate that further improvement of penicillin production remains a possibility,” the authors wrote. They noted that the newly available genome sequence will help to unravel the genetic changes that have accompanied the strain improvements achieved so far by classical methods.
And, the team predicted, by integrating additional metabolomic and proteomic information, it may be possible to improve antibiotic production even further. “Such ‘systems’ approaches will ultimately contribute to further improvement of this important cell factory via inverse metabolic engineering,” the researchers concluded.
The P. chrysogenum genome sequence has been deposited in EMBL.