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Title: Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms
Authors: Andersen, Jens Bo
Hultqvist, Louise Dahl
Jansen, Charlotte Uldahl
Jakobsen, Tim Holm
Nilsson, Martin
Rybtke, Morten
Uhd, Jesper
Fritz, Blaine Gabriel
Seifert, Roland
Berthelsen, Jens
Nielsen, Thomas Eiland
Qvortrup, Katrine
Givskov, Michael
Tolker-Nielsen, Tim
Keywords: Engineering::Environmental engineering
Science::Biological sciences
Issue Date: 2021
Source: Andersen, J. B., Hultqvist, L. D., Jansen, C. U., Jakobsen, T. H., Nilsson, M., Rybtke, M., Uhd, J., Fritz, B. G., Seifert, R., Berthelsen, J., Nielsen, T. E., Qvortrup, K., Givskov, M. & Tolker-Nielsen, T. (2021). Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms. Npj Biofilms and Microbiomes, 7(1), 59-.
Journal: npj Biofilms and Microbiomes 
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.
ISSN: 2055-5008
DOI: 10.1038/s41522-021-00225-4
Rights: © 2021 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
Fulltext Permission: open
Fulltext Availability: With Fulltext
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