A synthetic peptide sensitizes multi-drug resistant pseudomonas aeruginosa to antibiotics for more than two hours and permeabilizes its envelope for twenty hours
Background: Pseudomonas aeruginosa is a Gram-negative pathogen that frequently causes life-threatening infections in immunocompromised patients. We previously showed that subinhibitory concentrations of short synthetic peptides permeabilize P. aeruginosa and enhance the lethal action of co-administe...
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| Format: | info:eu-repo/semantics/article |
| Language: | spa |
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Springer
2023
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| Online Access: | https://hdl.handle.net/10171/65197 |
| _version_ | 1793400137001730048 |
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| author | Razquin-Olazaran, I. (Iosu) Shahrour, H. (Hawraa) Martinez-de-Tejada, G. (Guillermo) |
| author_facet | Razquin-Olazaran, I. (Iosu) Shahrour, H. (Hawraa) Martinez-de-Tejada, G. (Guillermo) |
| author_sort | Razquin-Olazaran, I. (Iosu) |
| collection | DSpace |
| description | Background: Pseudomonas aeruginosa is a Gram-negative pathogen that frequently causes life-threatening infections in immunocompromised patients. We previously showed that subinhibitory concentrations of short synthetic peptides permeabilize P. aeruginosa and enhance the lethal action of co-administered antibiotics.
Methods: Long-term permeabilization caused by exposure of multidrug-resistant P. aeruginosa strains to peptide P4–9 was investigated by measuring the uptake of several antibiotics and fluorescent probes and by using confocal imaging and atomic force microscopy.
Results: We demonstrated that P4–9, a 13-amino acid peptide, induces a growth delay (i.e. post-antibiotic effect) of 1.3 h on a multidrug-resistant P. aeruginosa clinical isolate. Remarkably, when an independently P4–9-treated culture was allowed to grow in the absence of the peptide, cells remained sensitive to subinhibitory concentrations of
antibiotics such as ceftazidime, fosfomycin and erythromycin for at least 2 h. We designated this persistent sensitization to antibiotics occurring in the absence of the sensitizing agent as Post-Antibiotic Effect associated Permeabilization (PAEP). Using atomic force microscopy, we showed that exposure to P4–9 induces profound
alterations on the bacterial surface and that treated cells need at least 2 h of growth to repair those lesions. During PAEP, P. aeruginosa mutants overexpressing either the efflux pump MexAB-OprM system or the AmpC β-lactamase were rendered sensitive to antibiotics that are known substrates of those mechanisms of resistance. Finally, we showed for the first time that the descendants of bacteria surviving exposure to a membrane disturbing peptide retain a significant level of permeability to hydrophobic compounds, including propidium iodide, even after 20 h of growth in the absence of the peptide.
Conclusions: The phenomenon of long-term sensitization to antibiotics shown here may have important therapeutic implications for a combined peptide-antibiotic treatment because the peptide would not need to be present to exert its antibiotic enhancing activity as long as the target organism retains sensitization to the antibiotic. |
| format | info:eu-repo/semantics/article |
| id | oai:dadun.unav.edu:10171-65197 |
| institution | Universidad de Navarra |
| language | spa |
| publishDate | 2023 |
| publisher | Springer |
| record_format | dspace |
| spelling | oai:dadun.unav.edu:10171-651972023-02-06T06:04:44Z A synthetic peptide sensitizes multi-drug resistant pseudomonas aeruginosa to antibiotics for more than two hours and permeabilizes its envelope for twenty hours Razquin-Olazaran, I. (Iosu) Shahrour, H. (Hawraa) Martinez-de-Tejada, G. (Guillermo) Antibiotic resistance Pseudomonas aeruginosa Antimicrobial peptide Post-antibiotic effect Permeability Background: Pseudomonas aeruginosa is a Gram-negative pathogen that frequently causes life-threatening infections in immunocompromised patients. We previously showed that subinhibitory concentrations of short synthetic peptides permeabilize P. aeruginosa and enhance the lethal action of co-administered antibiotics. Methods: Long-term permeabilization caused by exposure of multidrug-resistant P. aeruginosa strains to peptide P4–9 was investigated by measuring the uptake of several antibiotics and fluorescent probes and by using confocal imaging and atomic force microscopy. Results: We demonstrated that P4–9, a 13-amino acid peptide, induces a growth delay (i.e. post-antibiotic effect) of 1.3 h on a multidrug-resistant P. aeruginosa clinical isolate. Remarkably, when an independently P4–9-treated culture was allowed to grow in the absence of the peptide, cells remained sensitive to subinhibitory concentrations of antibiotics such as ceftazidime, fosfomycin and erythromycin for at least 2 h. We designated this persistent sensitization to antibiotics occurring in the absence of the sensitizing agent as Post-Antibiotic Effect associated Permeabilization (PAEP). Using atomic force microscopy, we showed that exposure to P4–9 induces profound alterations on the bacterial surface and that treated cells need at least 2 h of growth to repair those lesions. During PAEP, P. aeruginosa mutants overexpressing either the efflux pump MexAB-OprM system or the AmpC β-lactamase were rendered sensitive to antibiotics that are known substrates of those mechanisms of resistance. Finally, we showed for the first time that the descendants of bacteria surviving exposure to a membrane disturbing peptide retain a significant level of permeability to hydrophobic compounds, including propidium iodide, even after 20 h of growth in the absence of the peptide. Conclusions: The phenomenon of long-term sensitization to antibiotics shown here may have important therapeutic implications for a combined peptide-antibiotic treatment because the peptide would not need to be present to exert its antibiotic enhancing activity as long as the target organism retains sensitization to the antibiotic. 2023-01-30T12:48:24Z 2023-01-30T12:48:24Z 2020 info:eu-repo/semantics/article https://hdl.handle.net/10171/65197 spa FIS-PI050768 PIUNA-P2008–11 PIUNA-P2011– 17 info:eu-repo/semantics/openAccess application/pdf Springer |
| spellingShingle | Antibiotic resistance Pseudomonas aeruginosa Antimicrobial peptide Post-antibiotic effect Permeability Razquin-Olazaran, I. (Iosu) Shahrour, H. (Hawraa) Martinez-de-Tejada, G. (Guillermo) A synthetic peptide sensitizes multi-drug resistant pseudomonas aeruginosa to antibiotics for more than two hours and permeabilizes its envelope for twenty hours |
| title | A synthetic peptide sensitizes multi-drug resistant pseudomonas aeruginosa to antibiotics for more than two hours and permeabilizes its envelope for twenty hours |
| title_full | A synthetic peptide sensitizes multi-drug resistant pseudomonas aeruginosa to antibiotics for more than two hours and permeabilizes its envelope for twenty hours |
| title_fullStr | A synthetic peptide sensitizes multi-drug resistant pseudomonas aeruginosa to antibiotics for more than two hours and permeabilizes its envelope for twenty hours |
| title_full_unstemmed | A synthetic peptide sensitizes multi-drug resistant pseudomonas aeruginosa to antibiotics for more than two hours and permeabilizes its envelope for twenty hours |
| title_short | A synthetic peptide sensitizes multi-drug resistant pseudomonas aeruginosa to antibiotics for more than two hours and permeabilizes its envelope for twenty hours |
| title_sort | synthetic peptide sensitizes multi-drug resistant pseudomonas aeruginosa to antibiotics for more than two hours and permeabilizes its envelope for twenty hours |
| topic | Antibiotic resistance Pseudomonas aeruginosa Antimicrobial peptide Post-antibiotic effect Permeability |
| url | https://hdl.handle.net/10171/65197 |
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