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  3. 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

  • ACS Infect Dis. 2020 Jun 12;6(6):1460-1479. doi: 10.1021/acsinfecdis.0c00070.
Ardeshir Rineh 1 2,  Odel Soren 3 4 5,  Timothy McEwan 1 2,  Vikashini Ravikumar 6,  Wee Han Poh 6,  Fereshteh Azamifar 1 7,  M Reza Naimi-Jamal 7,  Chen-Yi Cheung 8,  Alysha G Elliott 9,  Johannes Zuegg 9,  Mark A T Blaskovich 9,  Matthew A Cooper 9,  Victoria Dolange 5,  Myron Christodoulides 5,  Gregory M Cook 8 10,  Scott A Rice 6 11 12,  Saul N Faust 4 5 13,  Jeremy S Webb 3 4 13,  Michael J Kelso 1 2
Affiliations

Affiliations

  • 1 Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, New South Wales 2522, Australia.
  • 2 Illawarra Health and Medical Research Institute, Wollongong, New South Wales 2522, Australia.
  • 3 Biological Sciences and Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom.
  • 4 National Biofilm Innovation Centre, University of Southampton, Southampton SO17 1BJ, United Kingdom.
  • 5 Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton SO16 6YD, United Kingdom.
  • 6 Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, 637551, Singapore.
  • 7 Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran.
  • 8 Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand.
  • 9 Community for Open Antimicrobial Drug Discovery, Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • 10 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1042, New Zealand.
  • 11 ithree Institute, University of Technology Sydney, Ultimo, New South Wales 2007, Australia.
  • 12 School of Biological Sciences, Nanyang Technological University, 637551, Singapore.
  • 13 NIHR Southampton Biomedical Research Centre and NIHR Southampton Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, United Kingdom.
PMID: 32329596 DOI: 10.1021/acsinfecdis.0c00070
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.

Keywords

Pseudomonas aeruginosa; biofilm; cephalosporin-3′-diazeniumdiolate; chronic infection; cystic fibrosis.

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