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

Bethany K. Okada, Anran Li, Mohammad R. Seyedsayamdost

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2005-2011
Number of pages7
JournalChemBioChem
Volume20
Issue number15
DOIs
StatePublished - 2019

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

Keywords

  • antivirulence agents
  • biosynthesis
  • guanfacine
  • natural products
  • quorum sensing

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