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In contrast, ATP synthase affects the ability of S. aureus to establish chronic infections and persist as small colony variants. In this study, we report that a synthetic small molecule, CP-20, is capable of dually inhibiting agr and ATP synthase. We demonstrate CP-20\u2019s ability to counteract key virulence phenotypes associated with both pathways, including hemolysis, biofilm formation, and antibiotic resistance. We also show that CP-20 facilitates more efficient clearance of S. aureus by murine macrophages than genetic inactivation of either agr or ATP synthase alone, suggesting that dual inhibition may have an additive effect on ablating intracellular survival. This work demonstrates the utility of a single chemical modulator to attenuate S. aureus pathogenesis via two nonessential pathways and suggests a pathway toward nonbactericidal virulence control.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00432","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:01:42Z","timestamp":1790190102000},"page":"3419-3429","source":"Crossref","is-referenced-by-count":1,"title":["A Small Molecule\nDual Inhibitor of\n                    <i>agr<\/i>\n                    Quorum Sensing and ATP Synthase\nBlocks Acute and Chronic Virulence\nPhenotypes in\n                    <i>Staphylococcus aureus<\/i>"],"prefix":"10.1021","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6407-7133","authenticated-orcid":true,"given":"Troy D.","family":"Vulpis","sequence":"first","affiliation":[{"name":"University of Wisconsin\u2212Madison , , 1101 University Ave. , , ,","place":["Madison, Wisconsin, United States, 53706"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan T.","family":"York","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2212Madison , , 1101 University Ave. , , ,","place":["Madison, Wisconsin, United States, 53706"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3208-313X","authenticated-orcid":true,"given":"A.P.","family":"Clay","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2212Madison , , 1101 University Ave. , , ,","place":["Madison, Wisconsin, United States, 53706"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Polaske","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2212Madison , , 1101 University Ave. , , ,","place":["Madison, Wisconsin, United States, 53706"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel W.","family":"Markovich","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2212Madison , , 1101 University Ave. , , ,","place":["Madison, Wisconsin, United States, 53706"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kijeong","family":"Lee","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2212Madison , , 1550 Linden Dr. , , ,","place":["Madison, Wisconsin, United States, 53706"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas H.","family":"Chang","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2212Madison , , 1415 Engineering Dr. , , ,","place":["Madison, Wisconsin, United States, 53706"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4917-5584","authenticated-orcid":true,"given":"Sean P.","family":"Palecek","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2212Madison , , 1415 Engineering Dr. , , ,","place":["Madison, Wisconsin, United States, 53706"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3140-8637","authenticated-orcid":true,"given":"David M.","family":"Lynn","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2212Madison , , 1101 University Ave. , , ,","place":["Madison, Wisconsin, United States, 53706"]},{"name":"University of Wisconsin\u2212Madison , , 1415 Engineering Dr. , , ,","place":["Madison, Wisconsin, United States, 53706"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9367-794X","authenticated-orcid":true,"given":"John-Demian","family":"Sauer","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2212Madison , , 1550 Linden Dr. , , ,","place":["Madison, Wisconsin, United States, 53706"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lloyd M.","family":"Smith","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2212Madison , , 1101 University Ave. , , ,","place":["Madison, Wisconsin, United States, 53706"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4261-8194","authenticated-orcid":true,"given":"Helen E.","family":"Blackwell","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2212Madison , , 1101 University Ave. , , ,","place":["Madison, Wisconsin, United States, 53706"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"issue":"3","key":"2026100909100194400_cit1","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1128\/CMR.00134-14","article-title":"Staphylococcus aureus infections:\nepidemiology, pathophysiology, clinical manifestations, and management","volume":"28","author":"Tong","year":"2015","journal-title":"Clin. 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Biol."},{"issue":"5\u20136","key":"2026100909100194400_cit18","doi-asserted-by":"publisher","DOI":"10.1002\/ijch.202200096","article-title":"Chemical\nand biomolecular insights into the Staphylococcus aureus agr quorum sensing system: Current\nprogress and ongoing challenges","volume":"63","author":"Polaske","year":"2023","journal-title":"Isr. J. Chem."},{"issue":"38","key":"2026100909100194400_cit19","doi-asserted-by":"publisher","first-page":"34736","DOI":"10.1074\/jbc.M205367200","article-title":"Transmembrane topology\nof AgrB, the protein involved in the post-translational modification\nof AgrD in Staphylococcus aureus","volume":"277","author":"Zhang","year":"2002","journal-title":"J. Biol. Chem."},{"issue":"34","key":"2026100909100194400_cit20","doi-asserted-by":"publisher","first-page":"10679","DOI":"10.1073\/pnas.1506030112","article-title":"Key driving forces\nin the biosynthesis of autoinducing peptides required for staphylococcal\nvirulence","volume":"112","author":"Wang","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"33","key":"2026100909100194400_cit21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2202661119","article-title":"Reconstitution of the S. aureus agr quorum sensing pathway reveals a direct role for\nthe integral membrane protease MroQ in pheromone biosynthesis","volume":"119","author":"Zhao","year":"2022","journal-title":"Proc. Natl. Acad. Sci. U. S. 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Genet."},{"issue":"10","key":"2026100909100194400_cit25","doi-asserted-by":"publisher","first-page":"3967","DOI":"10.1002\/j.1460-2075.1993.tb06074.x","article-title":"Synthesis of staphylococcal\nvirulene factors is controlled\nby a regulatory RNA molecule","volume":"12","author":"Novick","year":"1993","journal-title":"EMBO J."},{"key":"2026100909100194400_cit26","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1021\/cr100370n","article-title":"Peptide Signaling\nin the Staphylococci","volume":"111","author":"Thoendel","year":"2011","journal-title":"Chem. Rev."},{"issue":"5","key":"2026100909100194400_cit27","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1073\/pnas.0407661102","article-title":"Transient interference\nwith staphylococcal quorum sensing blocks abscess formation","volume":"102","author":"Wright","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. 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Agents Chemother."},{"issue":"4","key":"2026100909100194400_cit38","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1016\/j.chembiol.2021.12.005","article-title":"Identification\nof small molecules that strongly inhibit bacterial quorum sensing\nusing a high-throughput lipid vesicle lysis assay","volume":"29","author":"Polaske","year":"2022","journal-title":"Cell Chem. Biol."},{"issue":"9","key":"2026100909100194400_cit39","doi-asserted-by":"publisher","first-page":"9199","DOI":"10.1021\/jacs.5c21051","article-title":"A Small\nMolecule that Inhibits the Quorum Sensing Receptor AgrC in Staphylococcus aureus","volume":"148","author":"Polaske","year":"2026","journal-title":"J. Am. Chem.\nSoc."},{"issue":"24","key":"2026100909100194400_cit40","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202201798","article-title":"Sustained\nRelease of a Synthetic Autoinducing Peptide Mimetic Blocks Bacterial\nCommunication and Virulence In Vivo","volume":"61","author":"West","year":"2022","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026100909100194400_cit41","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.3389\/fmicb.2020.01415","article-title":"Intracellular\nEnvironment and agr System Affect Colony Size Heterogeneity\nof Staphylococcus aureus","volume":"11","author":"Haffner","year":"2020","journal-title":"Front.\nMicrobiol."},{"issue":"8","key":"2026100909100194400_cit42","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1086\/592051","article-title":"Prevalence of agr dysfunction among\ncolonizing Staphylococcus aureus strains","volume":"198","author":"Shopsin","year":"2008","journal-title":"J. Infect. 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