RESUMO
AIMS: To obtain the high-yield strain of fusidic acid, which is produced from fungus Fusidium coccineum and is the only fusidane-type antibiotic that has been used clinically, and confirm the changes in the transcription levels involved in increasing its production. METHODS AND RESULTS: By using the atmospheric and room temperature plasma mutagenesis technology, a high-yield mutant strain of fusidic acid-producing fungus F. coccineum was obtained. Using the genomic analysis of the original strain based on biosynthetic pathways of ergosterol and helvolic acid, we demonstrate that the pathway involved in the biosynthesis of 2,3-oxidosqualene from acetyl coenzyme A was shared by fusidic acid and ergosterol, and fusidic acid was finally synthesized by the catalysis of multiple cytochrome P450s and short-chain dehydrogenase/reductase from 2,3-oxidosqualene. Then, through the transcriptomic analysis of the original and mutagenized strain, it revealed that the proposed pathway from sucrose to fusidic acid was the most significantly up-regulated in the transcription levels of the mutant strain. CONCLUSIONS: The changes in the transcription levels of fusidic acid during its biosynthesis might result in high-yield of fusidic acid in the mutant strain. This is the first report on the whole biosynthetic pathway of fusidic acid in F. coccineum. SIGNIFICANCE AND IMPACT OF THE STUDY: This study obtain the genetic basis for the biosynthesis of fusidic acid which could be beneficial for the molecular modifications of F. coccineum to further increase its yield by fermentation in future, and established the foundation to reveal the mechanism of the high-yield of the mutant strain.
