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Cephalosporin nitric oxide-donor prodrug DEA-C3D disperses biofilms formed by clinical cystic fibrosis isolates of Pseudomonas aeruginosa

Journal Article


Abstract


  • © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. OBJECTIVES: The cephalosporin nitric oxide (NO)-donor prodrug DEA-C3D ('DiEthylAmin-Cephalosporin-3'-Diazeniumdiolate') has been shown to initiate the dispersal of biofilms formed by the Pseudomonas aeruginosa laboratory strain PAO1. In this study, we investigated whether DEA-C3D disperses biofilms formed by clinical cystic fibrosis (CF) isolates of P. aeruginosa and its effect in combination with two antipseudomonal antibiotics, tobramycin and colistin, in vitro. METHODS: β-Lactamase-triggered release of NO from DEA-C3D was confirmed using a gas-phase chemiluminescence detector. MICs for P. aeruginosa clinical isolates were determined using the broth microdilution method. A crystal violet staining technique and confocal laser scanning microscopy were used to evaluate the effects of DEA-C3D on P. aeruginosa biofilms alone and in combination with tobramycin and colistin. RESULTS: DEA-C3D was confirmed to selectively release NO in response to contact with bacterial β-lactamase. Despite lacking direct, cephalosporin/β-lactam-based antibacterial activity, DEA-C3D was able to disperse biofilms formed by three P. aeruginosa clinical isolates. Confocal microscopy revealed that DEA-C3D in combination with tobramycin produces similar reductions in biofilm to DEA-C3D alone, whereas the combination with colistin causes near complete eradication of P. aeruginosa biofilms in vitro. CONCLUSIONS: DEA-C3D is effective in dispersing biofilms formed by multiple clinical isolates of P. aeruginosa and could hold promise as a new adjunctive therapy to patients with CF.

Authors


  •   Soren, Odel (external author)
  •   Rineh, Ardeshir (external author)
  •   Silva, Diogo (external author)
  •   Cai, Yuming (external author)
  •   Howlin, Robert (external author)
  •   Allan, Raymond (external author)
  •   Feelisch, Martin (external author)
  •   Davies, Jane (external author)
  •   Connett, Gary (external author)
  •   Faust, Saul (external author)
  •   Kelso, Michael J.
  •   Webb, Jeremy (external author)

Publication Date


  • 2020

Citation


  • Soren, O., Rineh, A., Silva, D., Cai, Y., Howlin, R., Allan, R., Feelisch, M., Davies, J., Connett, G., Faust, S., Kelso, M. & Webb, J. (2020). Cephalosporin nitric oxide-donor prodrug DEA-C3D disperses biofilms formed by clinical cystic fibrosis isolates of Pseudomonas aeruginosa. Journal of Antimicrobial Chemotherapy, 75 (1), 117-125.

Scopus Eid


  • 2-s2.0-85076446438

Number Of Pages


  • 8

Start Page


  • 117

End Page


  • 125

Volume


  • 75

Issue


  • 1

Place Of Publication


  • United Kingdom

Abstract


  • © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. OBJECTIVES: The cephalosporin nitric oxide (NO)-donor prodrug DEA-C3D ('DiEthylAmin-Cephalosporin-3'-Diazeniumdiolate') has been shown to initiate the dispersal of biofilms formed by the Pseudomonas aeruginosa laboratory strain PAO1. In this study, we investigated whether DEA-C3D disperses biofilms formed by clinical cystic fibrosis (CF) isolates of P. aeruginosa and its effect in combination with two antipseudomonal antibiotics, tobramycin and colistin, in vitro. METHODS: β-Lactamase-triggered release of NO from DEA-C3D was confirmed using a gas-phase chemiluminescence detector. MICs for P. aeruginosa clinical isolates were determined using the broth microdilution method. A crystal violet staining technique and confocal laser scanning microscopy were used to evaluate the effects of DEA-C3D on P. aeruginosa biofilms alone and in combination with tobramycin and colistin. RESULTS: DEA-C3D was confirmed to selectively release NO in response to contact with bacterial β-lactamase. Despite lacking direct, cephalosporin/β-lactam-based antibacterial activity, DEA-C3D was able to disperse biofilms formed by three P. aeruginosa clinical isolates. Confocal microscopy revealed that DEA-C3D in combination with tobramycin produces similar reductions in biofilm to DEA-C3D alone, whereas the combination with colistin causes near complete eradication of P. aeruginosa biofilms in vitro. CONCLUSIONS: DEA-C3D is effective in dispersing biofilms formed by multiple clinical isolates of P. aeruginosa and could hold promise as a new adjunctive therapy to patients with CF.

Authors


  •   Soren, Odel (external author)
  •   Rineh, Ardeshir (external author)
  •   Silva, Diogo (external author)
  •   Cai, Yuming (external author)
  •   Howlin, Robert (external author)
  •   Allan, Raymond (external author)
  •   Feelisch, Martin (external author)
  •   Davies, Jane (external author)
  •   Connett, Gary (external author)
  •   Faust, Saul (external author)
  •   Kelso, Michael J.
  •   Webb, Jeremy (external author)

Publication Date


  • 2020

Citation


  • Soren, O., Rineh, A., Silva, D., Cai, Y., Howlin, R., Allan, R., Feelisch, M., Davies, J., Connett, G., Faust, S., Kelso, M. & Webb, J. (2020). Cephalosporin nitric oxide-donor prodrug DEA-C3D disperses biofilms formed by clinical cystic fibrosis isolates of Pseudomonas aeruginosa. Journal of Antimicrobial Chemotherapy, 75 (1), 117-125.

Scopus Eid


  • 2-s2.0-85076446438

Number Of Pages


  • 8

Start Page


  • 117

End Page


  • 125

Volume


  • 75

Issue


  • 1

Place Of Publication


  • United Kingdom