A limited number of antifungal drugs, the side-effect of clinical drugs and the emergence of resistance create an urgent need for new antifungal treatment agents. High-throughput drug screening and in-depth drug action mechanism analyzation are needed to address this problem. In this study, we identified that artemisinin and its derivatives possessed antifungal activity through a high-throughput screening of the FDA-approved drug library. Subsequently, drug-resistant strains construction, a molecular dynamics simulation and a transcription level analysis were used to investigate artemisinin’s action mechanism in Candida glabrata. Transcription factor pleiotropic drug resistance 1 (PDR1) was an important determinant of artemisinin’s sensitivity by regulating the drug efflux pump and ergosterol biosynthesis pathway, leading to mitochondrial dysfunction. This dysfunction was shown by a depolarization of the mitochondrial membrane potential, an enhancement of the mitochondrial membrane viscosity and an upregulation of the intracellular ROS level in fungi. The discovery shed new light on the development of antifungal agents and understanding artemisinin’s action mechanism.

BACKGROUND Natamycin, an antifungal agent, has been widely used as a food preservative and medicine for fungal disease therapy. Seed preculture plays a crucial role in natamycin production, while studies on the effects of seed morphology on natamycin biosynthesis and corresponding regulation approaches are still absent. RESULTS Correlation analyses among spore age, seed morphology and natamycin production showed that old spores tended to form larger mycelial pellets, which gave rise to a significant reduction of natamycin biosynthesis. To solve this problem, microparticle talc was added to regulate the mycelial morphology in seed preculture. Optimal talc addition led to small mycelial pellets with hairy superficial mycelia and loose structure, resulting in higher glucose‐6‐phosphate dehydrogenase activity and energy charge. The seed morphology regulation effectively improved the natamycin titer and decreased the culture time, especially for old spores (age 28 days), with a 1.7‐fold higher natamycin titer and 16.9% culture time reduction. Unfortunately, direct talc addition proved to be infeasible for natamycin fermentation in a 5 L fermentor, which was attributed to physical damage from rapid agitation and excessive talc crashing. Therefore, the morphology engineering strategy was preferred in the seed preculture process rather than formal fermentation for natamycin production. CONCLUSION The new strategy proposed in this study could not only improve natamycin production, but also reduced the culture time. Furthermore, this work could provide references for other biochemicals production by filamentous bacteria or fungi, which would be of great significance in industrial antibiotic fermentation. © 2021 Society of Chemical Industry

This work identified the role of microbial elicitors on ε-PL production and disclosed the underlying mechanism through analysis of gene transcription, key enzyme activities, and intracellular metabolite pools, including transcriptome and metabolome analysis. It was the first report for the inducing effects of the “microbial call” to Streptomyces albulus and ε-PL biosynthesis, and these elicitors could be potentially obtained from decayed fruits infected by Botrytis cinerea ; hence, this may be a way of turning a biohazard into bioproduct wealth.

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