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Here, we have employed our previously developed HiTES methodology to identify one such compound against the ESKAPE pathogen <jats:italic>Pseudomonas aeruginosa<\/jats:italic>. Rather than induce silent biosynthetic gene clusters, we used HiTES to suppress actively expressed virulence genes. By screening a library of 770 FDA\u2010approved drugs, we identified guanfacine, a clinical hypertension drug, as an antivirulence agent in <jats:italic>P.\u2005aeruginosa<\/jats:italic>. Follow\u2010up studies showed that guanfacine reduces biofilm formation and pyocycanin production without altering growth. Moreover, we identified a homologue of QseC, a sensor His kinase used by multiple pathogens to turn on virulence, as a target of guanfacine. Our studies suggest that guanfacine might be an attractive antivirulence lead in <jats:italic>P.\u2005aeruginosa<\/jats:italic> and provide a template for uncovering such molecules by screening for downregulators of actively expressed biosynthetic genes.<\/jats:p>","DOI":"10.1002\/cbic.201900129","type":"journal-article","created":{"date-parts":[[2019,3,30]],"date-time":"2019-03-30T04:32:53Z","timestamp":1553920373000},"page":"2005-2011","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Identification of the Hypertension Drug Guanfacine as an Antivirulence Agent in <i>Pseudomonas aeruginosa<\/i>"],"prefix":"10.1002","volume":"20","author":[{"given":"Bethany K.","family":"Okada","sequence":"first","affiliation":[{"name":"Department of Chemistry Princeton University  Princeton NJ 08544 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anran","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology Princeton University  Princeton NJ 08544 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2707-4854","authenticated-orcid":false,"given":"Mohammad R.","family":"Seyedsayamdost","sequence":"additional","affiliation":[{"name":"Department of Chemistry Princeton University  Princeton NJ 08544 USA"},{"name":"Department of Molecular Biology Princeton University  Princeton NJ 08544 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,7,3]]},"reference":[{"key":"e_1_2_7_1_1","unstructured":"\u00a0"},{"key":"e_1_2_7_2_2","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1038\/431899a","volume":"431","author":"Nathan C.","year":"2004","journal-title":"Nature"},{"key":"e_1_2_7_3_2","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1126\/science.1176667","volume":"325","author":"Fischbach M. 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