Stress-driven emergence of heritable non-genetic drug resistance

Stress-driven emergence of heritable non-genetic drug resistance | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article Stress-driven emergence of heritable non-genetic drug resistance Daniel Jarosz, Jing Lin Xie, Sifei Yin, Theodore Yang, Kiran Chandrasekher, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5744219/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Drug resistance is the chief cause of treatment failure for therapies targeting chronic and infectious diseases. Whether the emergence of resistance is accelerated by environmental exposure to low levels of therapeutics remains controversial. Here, we report a non-genetic mechanism of stress adaptation that promotes heritable resistance to the widely used antifungal drug fluconazole. In the human fungal pathogen Candida albicans, transient exposure to subtherapeutic fluconazole doses induces a protective response that we term para-resistance. Like conventional resistance mechanisms, para-resistance is heritable. However, it does not arise from genetic mutations and can revert spontaneously. Systematic analyses of para-resistant isolates suggest that its key regulators include the stress-activated MAP kinase Hog1, the histone deacetylase subunit Snt1, the chromatin regulator Rap1, and the Sko1 transcriptional factor. Notably, molecules that disrupt biomolecular condensation and prion propagation – crucial for the inheritance of protein assemblies – block the induction of para-resistance, whereas inhibiting histone deacetylases facilitates its induction. We find that para-resistance is common in clinical isolates and, remarkably, passage through the mammalian gut triggers its acquisition, compromising fluconazole’s therapeutic efficacy. Our work defines a pervasive, prion-like epigenetic mechanism of stress adaptation and highlights potential strategies to mitigate the rapid emergence of drug resistance. Biological sciences/Microbiology/Antimicrobials/Antimicrobial resistance Biological sciences/Microbiology/Fungi/Fungal biology Full Text Additional Declarations There is NO Competing Interest. Supplementary Files TableS4.xlsx Dataset 4 TableS6.xlsx Dataset 6 TableS7.xlsx Dataset 7 TableS8.xlsx Dataset 8 TableS5.xlsx Dataset 5 TableS10.xlsx Dataset 10 TableS9.xlsx Dataset 9 Xieetal.2024SupplementalFigures.pdf Extended Data 1-4 Xieetal.2024TableS13StrainsPlasmidsOligos.pdf Dataset 1-3 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5744219","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":412220337,"identity":"0eba5ed3-8b2b-463e-947f-8be612044298","order_by":0,"name":"Daniel 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