Stk1 is required for BlaR1-mediated broad-spectrum β-lactam resistance in epidemic-causing strains of Staphylococcus aureus

Stk1 is required for BlaR1-mediated broad-spectrum β-lactam resistance in epidemic-causing strains of Staphylococcus aureus | 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 Stk1 is required for BlaR1-mediated broad-spectrum β-lactam resistance in epidemic-causing strains of Staphylococcus aureus Som Chatterjee, Raymond Poon, Nidhi Satishkumar, Wesley Mosimann, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8331258/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Sensory induction of mecA expression plays a pivotal role in mediating broad-spectrum β-lactam resistance (BBR) of MRSA. In contemporary MRSA isolates, sensory induction of BBR originates at the membrane-localized BlaR1, which, upon detection of β-lactam drugs, triggers a signal transduction cascade that promotes mecA induction. We hereby showed that phosphorylation of BlaR1, mediated through the serine-threonine kinase, Stk1, stabilizes its membrane spanning state and localization, allowing for proper drug sensing and subsequent signal transduction events to occur, culminating in mecA-mediated BBR. Our results demonstrated that targeting Stk1 could potentiate synthetic lethality to β-lactams in the majority of naturally isolated strains of MRSA. We also presented the structural and kinetic basis for a Stk1-inhibitor complex that could enable rational design of Stk1 directed anti-MRSA therapeutics in the future. Our results reveal a unique and hitherto unknown role of the STK signaling pathway in bacterial protein stabilization in the cytosolic membrane. Biological sciences/Microbiology/Bacteriology Biological sciences/Microbiology/Antimicrobials Biological sciences/Microbiology/Bacteria/Bacterial physiology Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Supplementarytext.pdf Stk1 is required for BlaR1-mediated broad-spectrum β-lactam resistance in epidemic-causing strains of Staphylococcus aureus Supplementaryfigures.pdf Stk1 is required for BlaR1-mediated broad-spectrum β-lactam resistance in epidemic-causing strains of Staphylococcus aureus Cite Share Download PDF Status: Under Review 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-8331258","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":561937491,"identity":"2e222fc5-a69a-40bf-b6c7-1fe27457fc39","order_by":0,"name":"Som Chatterjee","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-7138-4449","institution":"University of Maryland, Baltimore","correspondingAuthor":true,"prefix":"","firstName":"Som","middleName":"","lastName":"Chatterjee","suffix":""},{"id":561937492,"identity":"5d493422-cfc6-42b9-a3b9-270bca9cd7a4","order_by":1,"name":"Raymond Poon","email":"","orcid":"","institution":"University of Maryland, Baltimore","correspondingAuthor":false,"prefix":"","firstName":"Raymond","middleName":"","lastName":"Poon","suffix":""},{"id":561937493,"identity":"8cc0808e-1d0d-4d3a-9379-6f3f278e7e9e","order_by":2,"name":"Nidhi Satishkumar","email":"","orcid":"","institution":"University of Maryland, Baltimore","correspondingAuthor":false,"prefix":"","firstName":"Nidhi","middleName":"","lastName":"Satishkumar","suffix":""},{"id":561937494,"identity":"8443e745-d52a-4036-84eb-95f75f675683","order_by":3,"name":"Wesley Mosimann","email":"","orcid":"","institution":"University of British Columbia","correspondingAuthor":false,"prefix":"","firstName":"Wesley","middleName":"","lastName":"Mosimann","suffix":""},{"id":561937495,"identity":"b85b0180-9185-4964-87af-7b2388f38e34","order_by":4,"name":"Vedangi Hayatnagarkar","email":"","orcid":"","institution":"University of Maryland, Baltimore","correspondingAuthor":false,"prefix":"","firstName":"Vedangi","middleName":"","lastName":"Hayatnagarkar","suffix":""},{"id":561937496,"identity":"9400c10d-49a9-4627-8a2c-670437746541","order_by":5,"name":"Vijay Hemmadi","email":"","orcid":"","institution":"University of Maryland, Baltimore","correspondingAuthor":false,"prefix":"","firstName":"Vijay","middleName":"","lastName":"Hemmadi","suffix":""},{"id":561937497,"identity":"f163dd66-bbea-4ce7-a360-60ed2d276863","order_by":6,"name":"Skyler Kuhn","email":"","orcid":"","institution":"National Institutes of Health","correspondingAuthor":false,"prefix":"","firstName":"Skyler","middleName":"","lastName":"Kuhn","suffix":""},{"id":561937498,"identity":"fd24f314-8972-4cea-bbe8-7abcdc7bdc7b","order_by":7,"name":"Aditi Chatterjee","email":"","orcid":"","institution":"University of Maryland, Baltimore","correspondingAuthor":false,"prefix":"","firstName":"Aditi","middleName":"","lastName":"Chatterjee","suffix":""},{"id":561937499,"identity":"77f1fe7c-9680-4f16-97a5-2057c3b66ab4","order_by":8,"name":"Liam Worrall","email":"","orcid":"","institution":"University of British Columbia","correspondingAuthor":false,"prefix":"","firstName":"Liam","middleName":"","lastName":"Worrall","suffix":""},{"id":561937500,"identity":"e4758ad0-64a2-413a-a6fd-d9ba85b9da5b","order_by":9,"name":"Nathan Manes","email":"","orcid":"","institution":"National Institutes of Health","correspondingAuthor":false,"prefix":"","firstName":"Nathan","middleName":"","lastName":"Manes","suffix":""},{"id":561937501,"identity":"5f250fb2-154a-4098-b2f1-089fed8aa6e3","order_by":10,"name":"J. 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