Fecha de publicación: 20/01/2025 Fuente: PubMed "microbial biotechnology" Synth Syst Biotechnol. 2024 Dec 24;10(2):381-390. doi: 10.1016/j.synbio.2024.12.008. eCollection 2025 Jun.ABSTRACTPneumocandin B0 (PB0) is a lipohexapeptide synthesized by Glarea lozoyensis and serves as the precursor for the widely used antifungal drug caspofungin acetate (Cancidas®). However, the low titer of PB0 results in fermentation and purification costs during caspofungin production, limiting its widespread clinical application. Here, we engineered an efficient PB0-producing strain of G. lozoyensis by systems metabolic engineering strategies, including multi-omics analysis and multilevel metabolic engineering. We overexpressed four rate-limiting enzymes: thioesterase GLHYD, two cytochrome P450s GLP450s, and chorismate synthase GLCS; knocked out two competing pathways responsible for producing 6-methylsalicylic acid and pyranidine E; and overexpressed the global transcriptional activator GLHYP. As a result, the PB0 titer increased by 108.7 % to 2.63 g/L at the shake-flask level through combinatorial strategies. Our study provides valuable insights into achieving high-level production of PB0 and offers general guidance for developing efficient fungal cell factories to produce polyketide synthase-non-ribosomal peptide synthetase hybrid metabolites.PMID:39830076 | PMC:PMC11742615 | DOI:10.1016/j.synbio.2024.12.008