Identification of the Hypertension Drug Guanfacine as an Antivirulence Agent in Pseudomonas aeruginosa.

TitleIdentification of the Hypertension Drug Guanfacine as an Antivirulence Agent in Pseudomonas aeruginosa.
Publication TypeJournal Article
Year of Publication2019
AuthorsOkada, BK, Li, A, Seyedsayamdost, MR
JournalChembiochem
Volume20
Issue15
Pagination2005-2011
Date Published2019 08 01
ISSN1439-7633
KeywordsAnti-Bacterial Agents, Antihypertensive Agents, Guanfacine, Humans, Microbial Sensitivity Tests, Molecular Structure, Pseudomonas aeruginosa, Virulence Factors
Abstract

<p>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.</p>

DOI10.1002/cbic.201900129
Alternate JournalChembiochem
PubMed ID30927315
PubMed Central IDPMC6814388
Grant ListDP2 AI124786 / AI / NIAID NIH HHS / United States