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

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

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.

0305-7453
Soren, Odel
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Rineh, Ardeshir
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Silva, Diogo G
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Cai, Yuming
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Howlin, Robert P
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Allan, Raymond N.
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Feelisch, Martin
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Davies, Jane C
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Connett, Gary J.
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Faust, Saul N.
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Kelso, Michael J.
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Webb, Jeremy S.
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Soren, Odel
36eafd44-c181-43e5-a9e3-b45fee755749
Rineh, Ardeshir
9b3b5d87-023c-49a3-9290-c793e4fa07c2
Silva, Diogo G
17618973-49bf-4e82-80e1-18c8d59600dc
Cai, Yuming
ec0ec21f-cb8d-4407-aed8-01da53182083
Howlin, Robert P
f3c84990-6196-47d4-ad8a-80954ea46c7f
Allan, Raymond N.
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Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Davies, Jane C
40856a00-592a-47a1-934e-6ffa051e4435
Connett, Gary J.
55d5676c-90d8-46bf-a508-62eded276516
Faust, Saul N.
f97df780-9f9b-418e-b349-7adf63e150c1
Kelso, Michael J.
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Webb, Jeremy S.
ec0a5c4e-86cc-4ae9-b390-7298f5d65f8d

Soren, Odel, Rineh, Ardeshir, Silva, Diogo G, Cai, Yuming, Howlin, Robert P, Allan, Raymond N., Feelisch, Martin, Davies, Jane C, Connett, Gary J., Faust, Saul N., Kelso, Michael J. and Webb, Jeremy S. (2019) Cephalosporin nitric oxide-donor prodrug DEA-C3D disperses biofilms formed by clinical cystic fibrosis isolates of Pseudomonas aeruginosa. Journal of Antimicrobial Chemotherapy. (doi:10.1093/jac/dkz378).

Record type: Article

Abstract

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.

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Accepted/In Press date: 2 August 2019
e-pub ahead of print date: 17 September 2019

Identifiers

Local EPrints ID: 436538
URI: http://eprints.soton.ac.uk/id/eprint/436538
ISSN: 0305-7453
PURE UUID: 9693cdce-d19a-4551-a3f7-71e928bcdd04
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158
ORCID for Gary J. Connett: ORCID iD orcid.org/0000-0003-1310-3239
ORCID for Saul N. Faust: ORCID iD orcid.org/0000-0003-3410-7642
ORCID for Jeremy S. Webb: ORCID iD orcid.org/0000-0003-2068-8589

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Date deposited: 12 Dec 2019 17:30
Last modified: 18 Feb 2021 17:36

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Contributors

Author: Odel Soren
Author: Ardeshir Rineh
Author: Diogo G Silva
Author: Yuming Cai
Author: Robert P Howlin
Author: Raymond N. Allan
Author: Martin Feelisch ORCID iD
Author: Jane C Davies
Author: Gary J. Connett ORCID iD
Author: Saul N. Faust ORCID iD
Author: Michael J. Kelso
Author: Jeremy S. Webb ORCID iD

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