Host cell-based screening assays for identification of molecules targeting Pseudomonas aeruginosa cyclic di-GMP signaling and biofilm formation
The rapid emergence of bacterial resistance to antibiotics in current use is occurring worldwide and poses a significant threat to global healthcare systems. Recent research to identify new effective anti-bacterial agents has focused on regulatory pathways as targets for interference. Regulatory mec...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-11-01
|
| Series: | Frontiers in Microbiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2023.1279922/full |
| _version_ | 1797614213949030400 |
|---|---|
| author | Ying Hu Jeremy Stephen Webb Shi-qi An |
| author_facet | Ying Hu Jeremy Stephen Webb Shi-qi An |
| author_sort | Ying Hu |
| collection | DOAJ |
| description | The rapid emergence of bacterial resistance to antibiotics in current use is occurring worldwide and poses a significant threat to global healthcare systems. Recent research to identify new effective anti-bacterial agents has focused on regulatory pathways as targets for interference. Regulatory mechanisms employing intracellular Bis-(3′,5′) cyclic di-guanylate (c-di-GMP) as a secondary messenger represent a distinct category of subjects. This molecule, c-di-GMP, is present in nearly all bacterial species and plays a pivotal role in governing various biological processes, encompassing antibiotic resistance, biofilm formation, and virulence. Alteration of the cellular concentrations of the nucleotide through modulation of associated signaling pathways has the potential to reduce biofilm formation or increase susceptibility of the biofilm bacteria to antibiotics. Here, we have developed a screen for compounds that alter c-di-GMP levels in Pseudomonas aeruginosa in co-culture with bronchial epithelial cells. Through the assay of 200 natural compounds, we were able to identify several substances showing promising effects on P. aeruginosa in a host biofilm infection model. Importantly, we detected compounds that inhibit c-di-GMP levels and showed significant influence on biofilm formation and virulence in P. aeruginosa in vitro and in vivo. Consequently, we offer proof-of-concept information regarding swift and practical drug screening assays, suitable for medium- to high-throughput applications, which target the c-di-GMP signaling pathways in this significant Gram-negative pathogen. |
| first_indexed | 2024-03-11T07:06:37Z |
| format | Article |
| id | doaj.art-77adc28db60f487c81641cadb50b21b2 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-03-11T07:06:37Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-77adc28db60f487c81641cadb50b21b22023-11-17T08:56:01ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2023-11-011410.3389/fmicb.2023.12799221279922Host cell-based screening assays for identification of molecules targeting Pseudomonas aeruginosa cyclic di-GMP signaling and biofilm formationYing HuJeremy Stephen WebbShi-qi AnThe rapid emergence of bacterial resistance to antibiotics in current use is occurring worldwide and poses a significant threat to global healthcare systems. Recent research to identify new effective anti-bacterial agents has focused on regulatory pathways as targets for interference. Regulatory mechanisms employing intracellular Bis-(3′,5′) cyclic di-guanylate (c-di-GMP) as a secondary messenger represent a distinct category of subjects. This molecule, c-di-GMP, is present in nearly all bacterial species and plays a pivotal role in governing various biological processes, encompassing antibiotic resistance, biofilm formation, and virulence. Alteration of the cellular concentrations of the nucleotide through modulation of associated signaling pathways has the potential to reduce biofilm formation or increase susceptibility of the biofilm bacteria to antibiotics. Here, we have developed a screen for compounds that alter c-di-GMP levels in Pseudomonas aeruginosa in co-culture with bronchial epithelial cells. Through the assay of 200 natural compounds, we were able to identify several substances showing promising effects on P. aeruginosa in a host biofilm infection model. Importantly, we detected compounds that inhibit c-di-GMP levels and showed significant influence on biofilm formation and virulence in P. aeruginosa in vitro and in vivo. Consequently, we offer proof-of-concept information regarding swift and practical drug screening assays, suitable for medium- to high-throughput applications, which target the c-di-GMP signaling pathways in this significant Gram-negative pathogen.https://www.frontiersin.org/articles/10.3389/fmicb.2023.1279922/fullantibiotic resistancec-di-GMPbiofilm formationPseudomonas aeruginosadrug screening |
| spellingShingle | Ying Hu Jeremy Stephen Webb Shi-qi An Host cell-based screening assays for identification of molecules targeting Pseudomonas aeruginosa cyclic di-GMP signaling and biofilm formation Frontiers in Microbiology antibiotic resistance c-di-GMP biofilm formation Pseudomonas aeruginosa drug screening |
| title | Host cell-based screening assays for identification of molecules targeting Pseudomonas aeruginosa cyclic di-GMP signaling and biofilm formation |
| title_full | Host cell-based screening assays for identification of molecules targeting Pseudomonas aeruginosa cyclic di-GMP signaling and biofilm formation |
| title_fullStr | Host cell-based screening assays for identification of molecules targeting Pseudomonas aeruginosa cyclic di-GMP signaling and biofilm formation |
| title_full_unstemmed | Host cell-based screening assays for identification of molecules targeting Pseudomonas aeruginosa cyclic di-GMP signaling and biofilm formation |
| title_short | Host cell-based screening assays for identification of molecules targeting Pseudomonas aeruginosa cyclic di-GMP signaling and biofilm formation |
| title_sort | host cell based screening assays for identification of molecules targeting pseudomonas aeruginosa cyclic di gmp signaling and biofilm formation |
| topic | antibiotic resistance c-di-GMP biofilm formation Pseudomonas aeruginosa drug screening |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2023.1279922/full |
| work_keys_str_mv | AT yinghu hostcellbasedscreeningassaysforidentificationofmoleculestargetingpseudomonasaeruginosacyclicdigmpsignalingandbiofilmformation AT jeremystephenwebb hostcellbasedscreeningassaysforidentificationofmoleculestargetingpseudomonasaeruginosacyclicdigmpsignalingandbiofilmformation AT shiqian hostcellbasedscreeningassaysforidentificationofmoleculestargetingpseudomonasaeruginosacyclicdigmpsignalingandbiofilmformation |