Comparative Proteomic Analysis of Acremonium chrysogenum Strains: Key Changes Converting the Wild-Type Strain into Antibiotic Cephalosporin C Biofactory

<i>Acremonium chrysogenum</i> is the only industrial producer of the antibiotic cephalosporin C (CPC), the starting substance for manufacturing cephalosporins of the first to fifth generations. Strains produced for industrial use are significantly improved by multiple rounds of random mutagenesis; however, the molecular basis for such changes is not fully understood. In this study, we attempt to elucidate key changes that occurred at the proteome level in the CSI program of <i>A. chrysogenum</i> HY (RNCM F-4081D), with CPC production 300-fold higher than that in the parental <i>A. chrysogenum</i> WT strain (ATCC 11550). Our work reveals that more than 30% of proteins are differentially expressed at different stages of fermentation. Among the identified changes, the most critical appears to be upregulation of beta-lactam biosynthetic enzymes. The data also suggest shifts in the primary metabolic pathways, providing building blocks for beta-lactam synthesis reactions, including the amino acid precursors cysteine and valine and the substrate for the expandase reaction, α-ketoglutarate. Changes in energy flows in favor of targeted metabolic pathways are also revealed. High-yielding CPC production appears to be accompanied by oxidative stress, as key oxidative stress enzymes are upregulated. Our findings are consistent with previous investigations describing changes that occurred in other fungal strains improved by classical methods. This points to general key changes leading to high-yield production. A deeper understanding of these features is important for predicting the target effects of improved industrial producers of secondary metabolites.