Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms

Jens Bo Andersen, Louise Dahl Hultqvist, Charlotte Uldahl Jansen, Tim Holm Jakobsen, Martin Nilsson, Morten Rybtke, Jesper Uhd, Blaine Gabriel Fritz, Roland Seifert, Jens Berthelsen, Thomas Eiland Nielsen, Katrine Qvortrup, Michael Givskov*, Tim Tolker-Nielsen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

9 Downloads (Pure)

Abstract

Microbial biofilms are involved in a number of infections that cannot be cured, as microbes in biofilms resist host immune defenses and antibiotic therapies. With no strict biofilm-antibiotic in the current pipelines, there is an unmet need for drug candidates that enable the current antibiotics to eradicate bacteria in biofilms. We used high-throughput screening to identify chemical compounds that reduce the intracellular c-di-GMP content in Pseudomonas aeruginosa. This led to the identification of a small molecule that efficiently depletes P. aeruginosa for c-di-GMP, inhibits biofilm formation, and disperses established biofilm. A combination of our lead compound with standard of care antibiotics showed improved eradication of an implant-associated infection established in mice. Genetic analyses provided evidence that the anti-biofilm compound stimulates the activity of the c-di-GMP phosphodiesterase BifA in P. aeruginosa. Our work constitutes a proof of concept for c-di-GMP phosphodiesterase-activating drugs administered in combination with antibiotics as a viable treatment strategy for otherwise recalcitrant infections.
Original languageEnglish
Article number59
JournalNPJ biofilms and microbiomes
Volume7
Issue number1
Number of pages13
ISSN2055-5008
DOIs
Publication statusPublished - 2021

Fingerprint

Dive into the research topics of 'Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms'. Together they form a unique fingerprint.

Cite this