Identification of the Hypertension Drug Guanfacine as an Antivirulence Agent in Pseudomonas aeruginosa. Author Bethany Okada, Anran Li, Mohammad Seyedsayamdost Publication Year 2019 Type Journal Article Abstract An alternative solution to the cyclical development of new antibiotics is the concept of disarming pathogens without affecting their growth, thereby eliminating the selective pressures that lead to resistant phenotypes. Here, we have employed our previously developed HiTES methodology to identify one such compound against the ESKAPE pathogen Pseudomonas aeruginosa. Rather than induce silent biosynthetic gene clusters, we used HiTES to suppress actively expressed virulence genes. By screening a library of 770 FDA-approved drugs, we identified guanfacine, a clinical hypertension drug, as an antivirulence agent in P. aeruginosa. Follow-up 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 P. aeruginosa and provide a template for uncovering such molecules by screening for downregulators of actively expressed biosynthetic genes. Keywords Pseudomonas aeruginosa, Anti-Bacterial Agents, Microbial Sensitivity Tests, Molecular Structure, Humans, Virulence Factors, Antihypertensive Agents, Guanfacine Journal Chembiochem Volume 20 Issue 15 Pages 2005-2011 Date Published 2019 Aug 01 ISSN Number 1439-7633 DOI 10.1002/cbic.201900129 Alternate Journal Chembiochem PMCID PMC6814388 PMID 30927315 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML