A permeability-increasing drug synergizes with bacterial efux pump inhibitors and restores susceptibility to antibiotics in multi-drug resistant Pseudomonas aeruginosa strains
Resistance to antibiotics poses a major global threat according to the World Health Organization. Restoring the activity of existing drugs is an attractive alternative to address this challenge. One of the most efficient mechanisms of bacterial resistance involves the expression of efflux pump syste...
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| Format: | info:eu-repo/semantics/article |
| Language: | eng |
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Springer Science and Business Media LLC
2021
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10171/62141 |
| _version_ | 1793400086682664960 |
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| author | Raquel Shahrour, H. (Hawraa) Pitts, B. (Betsey) Stewart, P.S. (Philip S.) Sánchez-Gómez, S. (Susana) Martinez-de-Tejada, G. (Guillermo) |
| author_facet | Raquel Shahrour, H. (Hawraa) Pitts, B. (Betsey) Stewart, P.S. (Philip S.) Sánchez-Gómez, S. (Susana) Martinez-de-Tejada, G. (Guillermo) |
| author_sort | Raquel |
| collection | DSpace |
| description | Resistance to antibiotics poses a major global threat according to the World Health Organization. Restoring the activity of existing drugs is an attractive alternative to address this challenge. One of the most efficient mechanisms of bacterial resistance involves the expression of efflux pump systems capable of expelling antibiotics from the cell. Although there are efflux pump inhibitors (EPIs) available, these molecules are toxic for humans. We hypothesized that permeability-increasing antimicrobial peptides (AMPs) could lower the amount of EPI necessary to sensitize bacteria to antibiotics that are efflux substrates. To test this hypothesis, we measured the ability of polymyxin B nonapeptide (PMBN), to synergize with antibiotics in the presence of EPIs. Assays were performed using planktonic and biofilm-forming cells of Pseudomonas aeruginosa strains overexpressing the MexAB-OprM efflux system. Synergy between PMBN and EPIs boosted azithromycin activity by a factor of 2,133 and sensitized P. aeruginosa to all tested antibiotics. This reduced several orders of magnitude the amount of inhibitor needed for antibiotic sensitization. The selected antibiotic-EPI-PMBN combination caused a 10 million-fold reduction in the viability of biofilm forming cells. We proved that AMPs can synergize with EPIs and that this phenomenon can be exploited to sensitize bacteria to antibiotics. |
| format | info:eu-repo/semantics/article |
| id | oai:dadun.unav.edu:10171-62141 |
| institution | Universidad de Navarra |
| language | eng |
| publishDate | 2021 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | oai:dadun.unav.edu:10171-621412022-11-28T11:34:03Z A permeability-increasing drug synergizes with bacterial efux pump inhibitors and restores susceptibility to antibiotics in multi-drug resistant Pseudomonas aeruginosa strains Raquel Shahrour, H. (Hawraa) Pitts, B. (Betsey) Stewart, P.S. (Philip S.) Sánchez-Gómez, S. (Susana) Martinez-de-Tejada, G. (Guillermo) Materias Investigacion::Ciencias de la Salud::Microbiología y biología molecular Resistance to antibiotics poses a major global threat according to the World Health Organization. Restoring the activity of existing drugs is an attractive alternative to address this challenge. One of the most efficient mechanisms of bacterial resistance involves the expression of efflux pump systems capable of expelling antibiotics from the cell. Although there are efflux pump inhibitors (EPIs) available, these molecules are toxic for humans. We hypothesized that permeability-increasing antimicrobial peptides (AMPs) could lower the amount of EPI necessary to sensitize bacteria to antibiotics that are efflux substrates. To test this hypothesis, we measured the ability of polymyxin B nonapeptide (PMBN), to synergize with antibiotics in the presence of EPIs. Assays were performed using planktonic and biofilm-forming cells of Pseudomonas aeruginosa strains overexpressing the MexAB-OprM efflux system. Synergy between PMBN and EPIs boosted azithromycin activity by a factor of 2,133 and sensitized P. aeruginosa to all tested antibiotics. This reduced several orders of magnitude the amount of inhibitor needed for antibiotic sensitization. The selected antibiotic-EPI-PMBN combination caused a 10 million-fold reduction in the viability of biofilm forming cells. We proved that AMPs can synergize with EPIs and that this phenomenon can be exploited to sensitize bacteria to antibiotics. 2021-10-04T10:47:10Z 2021-10-04T10:47:10Z 2019 info:eu-repo/semantics/article https://hdl.handle.net/10171/62141 eng info:eu-repo/semantics/openAccess application/pdf Springer Science and Business Media LLC |
| spellingShingle | Materias Investigacion::Ciencias de la Salud::Microbiología y biología molecular Raquel Shahrour, H. (Hawraa) Pitts, B. (Betsey) Stewart, P.S. (Philip S.) Sánchez-Gómez, S. (Susana) Martinez-de-Tejada, G. (Guillermo) A permeability-increasing drug synergizes with bacterial efux pump inhibitors and restores susceptibility to antibiotics in multi-drug resistant Pseudomonas aeruginosa strains |
| title | A permeability-increasing drug synergizes with bacterial efux pump inhibitors and restores susceptibility to antibiotics in multi-drug resistant Pseudomonas aeruginosa strains |
| title_full | A permeability-increasing drug synergizes with bacterial efux pump inhibitors and restores susceptibility to antibiotics in multi-drug resistant Pseudomonas aeruginosa strains |
| title_fullStr | A permeability-increasing drug synergizes with bacterial efux pump inhibitors and restores susceptibility to antibiotics in multi-drug resistant Pseudomonas aeruginosa strains |
| title_full_unstemmed | A permeability-increasing drug synergizes with bacterial efux pump inhibitors and restores susceptibility to antibiotics in multi-drug resistant Pseudomonas aeruginosa strains |
| title_short | A permeability-increasing drug synergizes with bacterial efux pump inhibitors and restores susceptibility to antibiotics in multi-drug resistant Pseudomonas aeruginosa strains |
| title_sort | permeability-increasing drug synergizes with bacterial efux pump inhibitors and restores susceptibility to antibiotics in multi-drug resistant pseudomonas aeruginosa strains |
| topic | Materias Investigacion::Ciencias de la Salud::Microbiología y biología molecular |
| url | https://hdl.handle.net/10171/62141 |
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