Bromotyrosine-Derived Metabolites from a Marine Sponge Inhibit <i>Pseudomonas aeruginosa</i> Biofilms
<i>Pseudomonas aeruginosa</i> forms stable biofilms, providing a major barrier for multiple classes of antibiotics and severely impairing treatment of infected patients. The biofilm matrix of this Gram-negative bacterium is primarily composed of three major exopolysaccharides: alginate,...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/12/10204 |
| _version_ | 1797594276238983168 |
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| author | Tam M. T. Tran Russell S. Addison Rohan A. Davis Bernd H. A. Rehm |
| author_facet | Tam M. T. Tran Russell S. Addison Rohan A. Davis Bernd H. A. Rehm |
| author_sort | Tam M. T. Tran |
| collection | DOAJ |
| description | <i>Pseudomonas aeruginosa</i> forms stable biofilms, providing a major barrier for multiple classes of antibiotics and severely impairing treatment of infected patients. The biofilm matrix of this Gram-negative bacterium is primarily composed of three major exopolysaccharides: alginate, Psl, and Pel. Here, we studied the antibiofilm properties of sponge-derived natural products ianthelliformisamines A–C and their combinations with clinically used antibiotics. Wild-type <i>P. aeruginosa</i> strain and its isogenic exopolysaccharide-deficient mutants were employed to determine the interference of the compounds with biofilm matrix components. We identified that ianthelliformisamines A and B worked synergistically with ciprofloxacin to kill planktonic and biofilm cells. Ianthelliformisamines A and B reduced the minimum inhibitory concentration (MIC) of ciprofloxacin to 1/3 and 1/4 MICs, respectively. In contrast, ianthelliformisamine C (MIC = 53.1 µg/mL) alone exhibited bactericidal effects dose-dependently on both free-living and biofilm populations of wild-type PAO1, PAO1Δ<i>pslA</i> (Psl deficient), PDO300 (alginate overproducing and mimicking clinical isolates), and PDO300Δ<i>alg8</i> (alginate deficient). Interestingly, the biofilm of the clinically relevant mucoid variant PDO300 was more susceptible to ianthelliformisamine C than strains with impaired polysaccharide synthesis. Ianthelliformisamines exhibited low cytotoxicity towards HEK293 cells in the resazurin viability assay. Mechanism of action studies showed that ianthelliformisamine C inhibited the efflux pump of <i>P. aeruginosa</i>. Metabolic stability analyses indicated that ianthelliformisamine C is stable and ianthelliformisamines A and B are rapidly degraded. Overall, these findings suggest that the ianthelliformisamine chemotype could be a promising candidate for the treatment of <i>P. aeruginosa</i> biofilms. |
| first_indexed | 2024-03-11T02:21:22Z |
| format | Article |
| id | doaj.art-661a3ee55f2c457797d77485ec06ba6e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T02:21:22Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-661a3ee55f2c457797d77485ec06ba6e2023-11-18T10:50:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-06-0124121020410.3390/ijms241210204Bromotyrosine-Derived Metabolites from a Marine Sponge Inhibit <i>Pseudomonas aeruginosa</i> BiofilmsTam M. T. Tran0Russell S. Addison1Rohan A. Davis2Bernd H. A. Rehm3Centre for Cell Factories and Biopolymers, Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, AustraliaPreclinical ADME/PK, Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, AustraliaNatureBank, Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, AustraliaCentre for Cell Factories and Biopolymers, Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, Australia<i>Pseudomonas aeruginosa</i> forms stable biofilms, providing a major barrier for multiple classes of antibiotics and severely impairing treatment of infected patients. The biofilm matrix of this Gram-negative bacterium is primarily composed of three major exopolysaccharides: alginate, Psl, and Pel. Here, we studied the antibiofilm properties of sponge-derived natural products ianthelliformisamines A–C and their combinations with clinically used antibiotics. Wild-type <i>P. aeruginosa</i> strain and its isogenic exopolysaccharide-deficient mutants were employed to determine the interference of the compounds with biofilm matrix components. We identified that ianthelliformisamines A and B worked synergistically with ciprofloxacin to kill planktonic and biofilm cells. Ianthelliformisamines A and B reduced the minimum inhibitory concentration (MIC) of ciprofloxacin to 1/3 and 1/4 MICs, respectively. In contrast, ianthelliformisamine C (MIC = 53.1 µg/mL) alone exhibited bactericidal effects dose-dependently on both free-living and biofilm populations of wild-type PAO1, PAO1Δ<i>pslA</i> (Psl deficient), PDO300 (alginate overproducing and mimicking clinical isolates), and PDO300Δ<i>alg8</i> (alginate deficient). Interestingly, the biofilm of the clinically relevant mucoid variant PDO300 was more susceptible to ianthelliformisamine C than strains with impaired polysaccharide synthesis. Ianthelliformisamines exhibited low cytotoxicity towards HEK293 cells in the resazurin viability assay. Mechanism of action studies showed that ianthelliformisamine C inhibited the efflux pump of <i>P. aeruginosa</i>. Metabolic stability analyses indicated that ianthelliformisamine C is stable and ianthelliformisamines A and B are rapidly degraded. Overall, these findings suggest that the ianthelliformisamine chemotype could be a promising candidate for the treatment of <i>P. aeruginosa</i> biofilms.https://www.mdpi.com/1422-0067/24/12/10204<i>Pseudomonas aeruginosa</i>biofilmsianthelliformisaminesspongenatural productalkaloid |
| spellingShingle | Tam M. T. Tran Russell S. Addison Rohan A. Davis Bernd H. A. Rehm Bromotyrosine-Derived Metabolites from a Marine Sponge Inhibit <i>Pseudomonas aeruginosa</i> Biofilms International Journal of Molecular Sciences <i>Pseudomonas aeruginosa</i> biofilms ianthelliformisamines sponge natural product alkaloid |
| title | Bromotyrosine-Derived Metabolites from a Marine Sponge Inhibit <i>Pseudomonas aeruginosa</i> Biofilms |
| title_full | Bromotyrosine-Derived Metabolites from a Marine Sponge Inhibit <i>Pseudomonas aeruginosa</i> Biofilms |
| title_fullStr | Bromotyrosine-Derived Metabolites from a Marine Sponge Inhibit <i>Pseudomonas aeruginosa</i> Biofilms |
| title_full_unstemmed | Bromotyrosine-Derived Metabolites from a Marine Sponge Inhibit <i>Pseudomonas aeruginosa</i> Biofilms |
| title_short | Bromotyrosine-Derived Metabolites from a Marine Sponge Inhibit <i>Pseudomonas aeruginosa</i> Biofilms |
| title_sort | bromotyrosine derived metabolites from a marine sponge inhibit i pseudomonas aeruginosa i biofilms |
| topic | <i>Pseudomonas aeruginosa</i> biofilms ianthelliformisamines sponge natural product alkaloid |
| url | https://www.mdpi.com/1422-0067/24/12/10204 |
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