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

• Main 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
• Other Authors: Singapore Centre for Environmental Life Sciences and Engineering
• Format: Article
• Language: English
• Published: 2021
• Subjects: Engineering::Environmental engineering; Science::Biological sciences; Antimicrobials; Biofilms
• Online Access: https://hdl.handle.net/10356/153814
• Institution: Nanyang Technological University

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.