Dual-targeting 5-nitroimidazole ethers eradicate H. pylori by induction of stress and disabling its adaptive response

Dual-targeting 5-nitroimidazole ethers eradicate H. pylori by induction of stress and disabling its adaptive response | 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 Article Dual-targeting 5-nitroimidazole ethers eradicate H. pylori by induction of stress and disabling its adaptive response Stephan Sieber, Michaela Fiedler, Ruolan Gong, Sonja Fuchs, Katharina Rox, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4497718/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Mar, 2026 Read the published version in Nature Microbiology → Version 1 posted You are reading this latest preprint version Abstract Metronidazole represents a front line-drug against Helicobacter pylori . To unravel its largely unknown cellular targets, we performed activity-based protein profiling (ABPP). Surprisingly, an alkynylated ether probe (Metro-P3) exhibited a 60-fold enhanced potency. Chaperonin HpGroEL and thiol peroxidase HpTpx were identified as prominent Metro-P3 targets, the latter of which is essential for H. pylori survival under oxidative stress. Biological assays validated HpTpx inhibition as the origin of the activity boost, demonstrated by covalent modification of the catalytic cysteine and co-crystallization. Metro-P3 and refined ether analogs exhibited favorable pharmacological profiles with no cytotoxicity. The activity boost translated to an in vivo H. pylori mouse model demonstrating full eradication at 50-fold reduced dosing compared to metronidazole triple therapy. Our results highlight 5-nitroimidazole ethers as dual mode of action antibiotics which induce oxidative stress and inhibit the stress response leading to bacterial death. Physical sciences/Chemistry/Chemical biology/Small molecules Physical sciences/Chemistry/Organic chemistry Biological sciences/Chemical biology/Target identification Full Text Additional Declarations Yes there is potential Competing Interest. Stephan Sieber is co-founder of smartbax limited. Supplementary Files SupplementaryInformationFiedleretalrevised.docx Supplementary Information for Dual-targeting 5-nitroimidazole ethers eradicate H. pylori by induction of stress and disabling its adaptive response Cite Share Download PDF Status: Published Journal Publication published 18 Mar, 2026 Read the published version in Nature Microbiology → 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. 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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-4497718","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":496687925,"identity":"bf9c9779-9d2c-4c96-b3f9-f9aade3a6aae","order_by":0,"name":"Stephan 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