Functional Genomics Resolves the Molecular Architecture of Antifungal Tolerance and Plant-Derived Synergy
** Lecture will be given in English**
Abstract:
Invasive fungal infections and escalating resistance severely compromise clinical efficacy, necessitating the discovery of novel therapeutic targets and agents. To comprehensively map functional vulnerabilities and discover synergistic compounds, we integrated high-throughput plant extract screening with genome-wide CRISPR interference (CRISPRi) profiling .
Under azole-induced stress in Saccharomyces cerevisiae, our screen defined distinct architectural modules governing survival. We demonstrate that adaptive fluconazole tolerance is driven by translational attenuation. Targeted repression of ribosome biogenesis components, notably RPS14A and RRB1, confers massive fitness advantages .
Parallel screening of 794 plant extracts identified tea seed and Gentiana lutea as potent inhibitors of Candida albicans proliferation, reducing growth by >40%. Functional interrogation of the plant phenolic ferulic acid (FA) linked its mechanism to ergosterol biosynthesis perturbation. Specifically, FA pressure upregulates HMG1 and HMG2, while ERG9 repression confers marked FA resistance. Crucially, FA exhibits potent synergy with fluconazole, reducing its minimal inhibitory concentration by approximately 8-fold in C. albicans and restoring susceptibility in azole-resistant strains. Furthermore, FA demonstrated dose-dependent lesion suppression in a Cochliobolus heterostrophus maize infection model .
Collectively, this combinatorial functional genomics approach delineates the molecular landscape of drug tolerance and validates plant-derived modulators as next-generation synergistic antifungal interventions.
