Epimutations driven by RNAi or heterochromatin evoke transient antimicrobial drug resistance in fungi

2025 · doi:10.1101/2025.06.17.660219
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Transient fungal drug resistance to FK506 arises from RNAi-dependent or heterochromatin-mediated silencing of the FKBP12 gene, with heterochromatic epimutants showing stability during infection.

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⚙ AI-generated deep summary by claude@2026-07, 2026-07-15 · read from full text ⓘ

The study investigated how members of the Mucor circinelloides species complex adapt to the antifungal natural product FK506, which targets calcineurin-dependent hyphal growth via FKBP12 (encoded by fkbA), focusing on whether FK506 resistance arises through genetic changes or epigenetic mechanisms. In Mucor bainieri, most FK506-resistant isolates were unstable and transient, reverting to drug sensitivity without associated DNA mutations, while half showed RNAi-dependent epimutations in which siRNAs silenced fkbA post-transcriptionally and a remaining subset showed heterochromatin-mediated repression involving H3K9 dimethylation. In the heterochromatic cases, siRNA enrichment at the fkbA locus was minimal, with evidence of distal siRNA spreading in some isolates; a similar heterochromatin/siRNA spreading mechanism was observed in Mucor atramentarius. The paper explicitly notes that epimutations can be stable during in vivo infection, but it does not provide a broader limitation on generalizability beyond the fungal models tested. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Antimicrobial resistance (AMR) is a global health threat emerging through microbe adaptation, driven by genetic variation, genome plasticity or epigenetic process. In this study, we investigated how the Mucor circinelloides species complex adapts to the antifungal natural product FK506, which binds to FKBP12 and inhibits calcineurin-dependent hyphal growth. In Mucor bainieri , most FK506-resistant isolates (90%) were found to be unstable and transient, readily reverting to drug sensitivity when passaged without drug, and with no associated DNA mutations. In half of the isolates (50%), FK506-resistance was conferred by RNAi-dependent epimutation in which small interfering RNAs (siRNAs) silenced the fkbA encoding FKBP12 post-transcriptionally. In contrast, most of the remaining FK506-resistant isolates (40%) were found to have undergone heterochromatin-mediated silencing via H3K9 dimethylation, transcriptionally repressing fkbA and neighboring genes. In these heterochromatic epimutants, only minimal enrichment of siRNA to the fkbA locus was observed, but in three of the four examples, siRNA was significantly enriched at a locus distant from fkbA . A similar mechanism operates in Mucor atramentarius , where FK506 resistance was mediated by ectopic heterochromatin silencing fkbA and associated genes with siRNA spreading across the region. Heterochromatin-mediated fkbA epimutants exhibited stability during in vivo infection, suggesting epimutation could impact pathogenesis. These findings reveal that antifungal resistance arising through distinct, transient epimutation pathways involving RNAi or heterochromatin, highlighting adaptive AMR strategies employed by ubiquitous eukaryotic microbes.
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Abstract Antimicrobial resistance (AMR) is a global health threat emerging through microbe adaptation, driven by genetic variation, genome plasticity or epigenetic process. In this study, we investigated how the Mucor circinelloides species complex adapts to the antifungal natural product FK506, which binds to FKBP12 and inhibits calcineurin-dependent hyphal growth. In Mucor bainieri, most FK506-resistant isolates (90%) were found to be unstable and transient, readily reverting to drug sensitivity when passaged without drug, and with no associated DNA mutations. In half of the isolates (50%), FK506-resistance was conferred by RNAi-dependent epimutation in which small interfering RNAs (siRNAs) silenced the fkbA encoding FKBP12 post-transcriptionally. In contrast, most of the remaining FK506-resistant isolates (40%) were found to have undergone heterochromatin-mediated silencing via H3K9 dimethylation, transcriptionally repressing fkbA and neighboring genes. In these heterochromatic epimutants, only minimal enrichment of siRNA to the fkbA locus was observed, but in three of the four examples, siRNA was significantly enriched at a locus distant from fkbA. A similar mechanism operates in Mucor atramentarius, where FK506 resistance was mediated by ectopic heterochromatin silencing fkbA and associated genes with siRNA spreading across the region. Heterochromatin-mediated fkbA epimutants exhibited stability during in vivo infection, suggesting epimutation could impact pathogenesis. These findings reveal that antifungal resistance arising through distinct, transient epimutation pathways involving RNAi or heterochromatin, highlighting adaptive AMR strategies employed by ubiquitous eukaryotic microbes. Competing Interest Statement The authors have declared no competing interest. Footnotes We performed several additional analyses and experiments, substantially expanding the manuscript and adding Figure 7 and Supplementary Figures 11-14. We have also added Carlos as a co-author in recognition of his contributions to the revised manuscript.

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