Son Ye-Eun, Heitman Joseph
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
bioRxiv. 2025 Jul 11:2025.06.17.660219. doi: 10.1101/2025.06.17.660219.
Antimicrobial resistance is a global health threat emerging through microbe adaptation, driven by genetic variation, genome plasticity or epigenetic regulation. This study investigates how the species complex adapts to the antifungal natural product FK506. In , most resistant strains exhibit unstable phenotypes without genetic changes. Approximately ~50% of FK506-resistant isolates acquire resistance via RNAi-dependent epimutation, where small interfering RNAs (siRNAs) silence transcription. The remaining isolates undergo heterochromatin-mediated silencing via H3K9 methylation and siRNAs spreading, repressing and neighboring genes. One isolate retained only heterochromatin marks without detectable siRNAs. A similar mechanism operates in , where FK506 resistance is mediated by ectopic heterochromatin associated with siRNA. Strikingly, heterochromatin-based epimutation inheritance remains stable following infection. These findings reveal that antifungal resistance can arise through distinct, heritable epigenetic pathways involving RNAi, heterochromatin, or both highlighting adaptive strategies employed by ubiquitous eukaryotic microbial pathogens infecting humans.
抗菌耐药性是一种全球健康威胁，它通过微生物适应而出现，由基因变异、基因组可塑性或表观遗传调控驱动。本研究调查了该物种复合体如何适应抗真菌天然产物FK506。在 中，大多数耐药菌株表现出不稳定的表型且无基因变化。约50%的FK506耐药分离株通过RNAi依赖的表观突变获得耐药性，其中小干扰RNA（siRNAs）使 转录沉默。其余分离株通过H3K9甲基化和siRNAs扩散进行异染色质介导的沉默，抑制 和邻近基因。一个分离株仅保留了异染色质标记而未检测到siRNAs。在 中存在类似机制，其中FK506耐药性由与siRNA相关的异位异染色质介导。引人注目的是，基于异染色质的表观突变遗传在 感染后仍保持稳定。这些发现揭示了抗真菌耐药性可通过涉及RNAi、异染色质或两者的不同可遗传表观遗传途径产生，突出了感染人类的普遍存在的真核微生物病原体所采用的适应性策略。
