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Discovery of cephalosporin-3´-diazeniumdiolates that show dual antibacterial and antibiofilm effects against Pseudomonas aeruginosa clinical cystic fibrosis isolates and efficacy in a Murine Respiratory Infection Model

Discovery of cephalosporin-3´-diazeniumdiolates that show dual antibacterial and antibiofilm effects against Pseudomonas aeruginosa clinical cystic fibrosis isolates and efficacy in a Murine Respiratory Infection Model
Discovery of cephalosporin-3´-diazeniumdiolates that show dual antibacterial and antibiofilm effects against Pseudomonas aeruginosa clinical cystic fibrosis isolates and efficacy in a Murine Respiratory Infection Model

The formation of biofilms provides a formidable defense for many bacteria against antibiotics and host immune responses. As a consequence, biofilms are thought to be the root cause of most chronic infections, including those occurring on medical indwelling devices, endocarditis, urinary tract infections, diabetic and burn wounds and bone and joint infections. In cystic fibrosis (CF), chronic Pseudomonas aeruginosa respiratory infections are the leading cause of morbidity and mortality in adults. Previous studies have shown that many bacteria can undergo a coordinated dispersal event in the presence of low concentrations of nitric oxide (NO), suggesting that NO could be used to trigger biofilm dispersal in chronic infections and enable clearance of the more vulnerable planktonic cells. In this proof-of-principle study, we describe efforts to create 'all-in-one' cephalosporin-based NO donor prodrugs (cephalosporin-3´-diazeniumdiolates, C3Ds) that show both direct beta-lactam mediated antibacterial activity and NO-induced antibiofilm effects. Twelve novel C3Ds were synthesized and screened against a panel of P. aeruginosa CF clinical isolates and other human pathogens. The most active compound, AMINOPIP2-ceftazidime 12, showed higher antibacterial potency than its parent cephalosporin and front-line antipseudomonal antibiotic ceftazidime, good stability against beta-lactamases, activity against ceftazidime-resistant P. aeruginosa in vitro biofilms and efficacy equivalent to ceftazidime in a murine P. aeruginosa respiratory infection model. The results support further evaluation of AMINOPIP2-ceftazidime 12 for P. aeruginosa lung infections in CF and broader study of 'all-in-one' C3Ds for other chronic infections.

2373-8227
Rineh, Ardeshir
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Soren, Odel
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Ravikumar, Vikashini
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Poh, Wee Han
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Azamifar, Fereshteh
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Naimi-Jamal, Mohammad Reza
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Cheung, Chen-Yi
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Elliott, Alysha G.
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Zuegg, Johannes
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Blaskovich, Mark Arnold Thomas
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Cooper, Matthew A.
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Dolange, Victoria
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Christodoulides, Myron
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Cook, Gregory M.
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Rice, Scott A.
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Faust, Saul N.
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Webb, Jeremy S.
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Kelso, Michael J.
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Rineh, Ardeshir
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Soren, Odel
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Ravikumar, Vikashini
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Poh, Wee Han
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Azamifar, Fereshteh
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Naimi-Jamal, Mohammad Reza
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Cheung, Chen-Yi
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Elliott, Alysha G.
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Zuegg, Johannes
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Blaskovich, Mark Arnold Thomas
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Cooper, Matthew A.
d639b267-6d24-4b70-9599-ea125c3d5f58
Dolange, Victoria
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Christodoulides, Myron
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Cook, Gregory M.
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Rice, Scott A.
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Faust, Saul N.
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Webb, Jeremy S.
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Kelso, Michael J.
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Rineh, Ardeshir, Soren, Odel, Ravikumar, Vikashini, Poh, Wee Han, Azamifar, Fereshteh, Naimi-Jamal, Mohammad Reza, Cheung, Chen-Yi, Elliott, Alysha G., Zuegg, Johannes, Blaskovich, Mark Arnold Thomas, Cooper, Matthew A., Dolange, Victoria, Christodoulides, Myron, Cook, Gregory M., Rice, Scott A., Faust, Saul N., Webb, Jeremy S. and Kelso, Michael J. (2020) Discovery of cephalosporin-3´-diazeniumdiolates that show dual antibacterial and antibiofilm effects against Pseudomonas aeruginosa clinical cystic fibrosis isolates and efficacy in a Murine Respiratory Infection Model. ACS Infectious Diseases. (doi:10.1021/acsinfecdis.0c00070).

Record type: Article

Abstract

The formation of biofilms provides a formidable defense for many bacteria against antibiotics and host immune responses. As a consequence, biofilms are thought to be the root cause of most chronic infections, including those occurring on medical indwelling devices, endocarditis, urinary tract infections, diabetic and burn wounds and bone and joint infections. In cystic fibrosis (CF), chronic Pseudomonas aeruginosa respiratory infections are the leading cause of morbidity and mortality in adults. Previous studies have shown that many bacteria can undergo a coordinated dispersal event in the presence of low concentrations of nitric oxide (NO), suggesting that NO could be used to trigger biofilm dispersal in chronic infections and enable clearance of the more vulnerable planktonic cells. In this proof-of-principle study, we describe efforts to create 'all-in-one' cephalosporin-based NO donor prodrugs (cephalosporin-3´-diazeniumdiolates, C3Ds) that show both direct beta-lactam mediated antibacterial activity and NO-induced antibiofilm effects. Twelve novel C3Ds were synthesized and screened against a panel of P. aeruginosa CF clinical isolates and other human pathogens. The most active compound, AMINOPIP2-ceftazidime 12, showed higher antibacterial potency than its parent cephalosporin and front-line antipseudomonal antibiotic ceftazidime, good stability against beta-lactamases, activity against ceftazidime-resistant P. aeruginosa in vitro biofilms and efficacy equivalent to ceftazidime in a murine P. aeruginosa respiratory infection model. The results support further evaluation of AMINOPIP2-ceftazidime 12 for P. aeruginosa lung infections in CF and broader study of 'all-in-one' C3Ds for other chronic infections.

Text
Kelso et al ACS Infect Dis - Revised Manuscript - Final Version 240420 - Accepted Manuscript
Restricted to Repository staff only until 24 April 2021.
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Accepted/In Press date: 24 April 2020
e-pub ahead of print date: 24 April 2020

Identifiers

Local EPrints ID: 439757
URI: http://eprints.soton.ac.uk/id/eprint/439757
ISSN: 2373-8227
PURE UUID: e45320ea-9548-453e-b204-996df4361307
ORCID for Myron Christodoulides: ORCID iD orcid.org/0000-0002-9663-4731
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: 01 May 2020 16:37
Last modified: 18 Feb 2021 17:08

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Contributors

Author: Ardeshir Rineh
Author: Odel Soren
Author: Vikashini Ravikumar
Author: Wee Han Poh
Author: Fereshteh Azamifar
Author: Mohammad Reza Naimi-Jamal
Author: Chen-Yi Cheung
Author: Alysha G. Elliott
Author: Johannes Zuegg
Author: Mark Arnold Thomas Blaskovich
Author: Matthew A. Cooper
Author: Victoria Dolange
Author: Gregory M. Cook
Author: Scott A. Rice
Author: Saul N. Faust ORCID iD
Author: Jeremy S. Webb ORCID iD
Author: Michael J. Kelso

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