Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms
| العنوان: | Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms |
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| المؤلفون: | Thomas E. Nielsen, Charlotte Uldahl Jansen, Tim Holm Jakobsen, Martin Nilsson, Blaine Gabriel Fritz, Morten Rybtke, Tim Tolker-Nielsen, Jens Berthelsen, Katrine Qvortrup, Michael Givskov, Roland Seifert, Jesper Uhd, Louise Dahl Hultqvist, Jens Bo Andersen |
| المساهمون: | Singapore Centre for Environmental Life Sciences and Engineering |
| المصدر: | NPJ Biofilms and Microbiomes 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, vol. 7, no. 1, 59 . https://doi.org/10.1038/s41522-021-00225-4 npj Biofilms and Microbiomes, Vol 7, Iss 1, Pp 1-13 (2021) 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, vol. 7, 59 . https://doi.org/10.1038/s41522-021-00225-4 |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Drug, medicine.medical_specialty, medicine.drug_class, media_common.quotation_subject, Antibiotics, medicine.disease_cause, Applied Microbiology and Biotechnology, Microbiology, Article, Microbial ecology, Mice, 03 medical and health sciences, Immune system, Medical microbiology, Tandem Mass Spectrometry, Drug Discovery, medicine, Animals, Cyclic GMP, Chromatography, High Pressure Liquid, 030304 developmental biology, media_common, 0303 health sciences, Dose-Response Relationship, Drug, biology, Antimicrobials, 030306 microbiology, Pseudomonas aeruginosa, Chemistry, Gene Expression Profiling, QR100-130, Biofilm, High-Throughput Nucleotide Sequencing, Biological sciences [Science], Gene Expression Regulation, Bacterial, biochemical phenomena, metabolism, and nutrition, Antimicrobial, biology.organism_classification, Anti-Bacterial Agents, Environmental engineering [Engineering], Biofilms, Transcriptome, Bacteria, Signal Transduction, Biotechnology |
| الوصف: | 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. Published version 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 Forschungsgemeinschaft. We acknowledge NIH grant #P30DK089507 for the use of P. aeruginosa mutant strains from the University of Washington Transposon Mutant Collection. |
| وصف الملف: | application/pdf |
| تدمد: | 2055-5008 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c3cd75c646b054eea7cfd2397b096e41 https://doi.org/10.1038/s41522-021-00225-4 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c3cd75c646b054eea7cfd2397b096e41 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20555008 |
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