TY - JOUR

T1 - Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms

AU - Andersen, Jens Bo

AU - Hultqvist, Louise Dahl

AU - Jansen, Charlotte Uldahl

AU - Jakobsen, Tim Holm

AU - Nilsson, Martin

AU - Rybtke, Morten

AU - Uhd, Jesper

AU - Fritz, Blaine Gabriel

AU - Seifert, Roland

AU - Berthelsen, Jens

AU - Nielsen, Thomas Eiland

AU - Qvortrup, Katrine

AU - Givskov, Michael

AU - Tolker-Nielsen, Tim

N1 - Funding Information: This work was supported by grants to M.G. and T.T.N. from the Danish Council for Independent Research, the Lundbeck Foundation, the Novo Nordisk Foundation, and the Danish Ministry of Higher Education and Science (the DK-Openscreen program). Work by R.S. was supported by the Priority Programme “Nucleotide Second Messenger Signaling in Bacteria” (SPP 1879) of the Deutsche Forschungsge-meinschaft. We acknowledge NIH grant #P30DK089507 for the use of P. aeruginosa mutant strains from the University of Washington Transposon Mutant Collection. Publisher Copyright: © 2021, The Author(s).

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1038/s41522-021-00225-4

DO - 10.1038/s41522-021-00225-4

M3 - Journal article

C2 - 34244523

AN - SCOPUS:85109786734

VL - 7

JO - n p j Biofilms and Microbomes

JF - n p j Biofilms and Microbomes

SN - 2055-5008

M1 - 59

ER -