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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 (P. 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 initiate biofilm dispersal in chronic infections, enabling clearance of the more vulnerable planktonic cells. In this study, we describe efforts to create "all-in-one"cephalosporin-based NO donor prodrugs (cephalosporin-3′-diazeniumdiolates, C3Ds) that show both direct β-lactam mediated antibacterial activity and 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 ((Z)-1-(4-(2-aminoethyl)piperidin-1-yl)-2-(((6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methoxy)diazene 1-oxide)-ceftazidime 12, showed higher antibacterial potency than its parent cephalosporin and front-line antipseudomonal antibiotic ceftazidime, good stability against β-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 a broader study of "all-in-one"C3Ds for other chronic infections.

Pseudomonas aeruginosa, biofilm, cephalosporin-3′-diazeniumdiolate, chronic infection, cystic fibrosis
2373-8227
1460-1479
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.
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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, 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, 6 (6), 1460-1479. (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 (P. 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 initiate biofilm dispersal in chronic infections, enabling clearance of the more vulnerable planktonic cells. In this study, we describe efforts to create "all-in-one"cephalosporin-based NO donor prodrugs (cephalosporin-3′-diazeniumdiolates, C3Ds) that show both direct β-lactam mediated antibacterial activity and 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 ((Z)-1-(4-(2-aminoethyl)piperidin-1-yl)-2-(((6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methoxy)diazene 1-oxide)-ceftazidime 12, showed higher antibacterial potency than its parent cephalosporin and front-line antipseudomonal antibiotic ceftazidime, good stability against β-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 a broader study of "all-in-one"C3Ds for other chronic infections.

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Kelso et al ACS Infect Dis - Revised Manuscript - Final Version 240420 - Accepted Manuscript
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Accepted/In Press date: 24 April 2020
e-pub ahead of print date: 24 April 2020
Published date: 12 June 2020
Additional Information: Funding Information: M.J.K. and S.A.R. thank the Australian Cystic Fibrosis Research Trust (ACFRT) for generously funding this work. We also thank the National Institutes for Allergy and Infectious Diseases (NIAID, USA) for their contributions to MIC testing and Lynn Miesel and her team at Pharmacology Discovery Services (Eurofins) Taiwan Ltd. for performing the mouse respiratory infection model. V.R., W.H.P., and S.A.R. acknowledge financial support from the Singapore Centre for Environmental Life Sciences Engineering, whose research is supported by the National Research Foundation Singapore, Ministry of Education, Nanyang Technological University and National University of Singapore, under its Research Centre of Excellence Programme. Antibacterial screening performed by CO-ADD (The Community for Antimicrobial Drug Discovery) was funded by the Wellcome Trust (UK) and The University of Queensland (Australia). CO-ADD acknowledges Compounds Australia ( griffith.edu.au/griffith-sciences/compounds-australia ) for their provision of specialized compound management and logistics research services to the project, ACRF and NCRIS for their funding support of the facility, and the Australian Red Cross Blood Service for the supply of blood for haemolysis assays. M.A.T.B., A.G.E., and J.Z. were supported in part by Wellcome Trust Strategic Award 104797/Z/14/Z. M.A.C. is a NHMRC Principal Research Fellow (APP1059354) and holds a fractional professorial research fellow appointment at The University of Queensland, with his remaining time as CEO of Inflazome Ltd., a company developing drugs to address clinical unmet needs in inflammatory disease. G.M.C. acknowledges funding from the New Zealand Health Research Council. O.S., S.N.F., and J.S.W. receive support from the NIHR Southampton Biomedical Research Centre and NIHR Southampton Clinical Research Facility and from the UK National Biofilm Innovation Centre, an Innovation and Knowledge Centre funded by the Biotechnology and Biological Sciences Research Council, Innovate UK, and Hartree Centre (Award Number BB/R012415/1). Publisher Copyright: © 2020 American Chemical Society.
Keywords: Pseudomonas aeruginosa, biofilm, cephalosporin-3′-diazeniumdiolate, chronic infection, cystic fibrosis

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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: 17 Mar 2024 05:31

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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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