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Chembiochem. 2019 Mar 30. doi: 10.1002/cbic.201900129. [Epub ahead of print]

Identification of the Hypertension Drug Guanfacine as an Anti-virulence Agent in Pseudomonas aeruginosa.

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Princeton University, UNITED STATES.
Princeton University, Chemistry, Washington University, Frick Chemistry Lab, Room 333, 08544, Princeton, UNITED STATES.


An alternative solution to the cyclical development of new antibiotics is the concept of disarming pathogens without affecting growth, thereby eliminating selective pressures that lead to resistant phenotypes. Herein, we employ 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 anti-virulence agent in P. aeruginosa. Follow-up studies showed that guanfacine reduces biofilm formation and pyocycanin production without affecting growth. Moreover, we identified a homolog of QseC, a sensor His kinase used by multiple pathogens to turn on virulence, as a target of guanfacine. Our studies suggest that guanfacine may be an attractive anti-virulence lead in P. aeruginosa and provide a template for identifying such molecules by screening for down-regulators of actively expressed biosynthetic genes.


natural products antibiotics quorum sensing anti-virulence Pseudomonas aeruginosa


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