Bacteria encased in biofilms are up to 1000x more resistant to antibiotics than their planktonic counterparts. It is thought that all chronic bacterial infections are biofilm-mediated and there are currently no effective drugs for treating such infections. Biofilm dispersing cephalosporin-3′-diazeniumdiolate (C3D) nitric oxide (NO)-donor prodrugs show great promise as potential new therapeutics for addressing chronic infections. Our original 1st-generation C3D's were specifically designed to be locally activated to release biofilm-dispersing NO following reactions with bacterial β-lactamases. However, a shortcoming of this approach is that the compounds could only be used against β-lactamase expressing biofilms, and the requirement for co-treatment with a standard of care antibiotic would complicate clinical development. A more appealing strategy would be to create C3Ds with increased β-lactamase stability and enhanced reactivity towards penicillin binding proteins (PBPs), the bactericidal target of all broad spectrum β-lactam antibiotics, because reaction with PBPs also releases NO from C3Ds. This presentation will describe the development of prototypical ‘all-in-one’ C3Ds that show dual antibacterial and biofilm dispersing properties. Our lead C3D, AMINOPIP2-ceftazidime, shows higher antibacterial activity than its parent (non-NO donor) cephalosporin antibiotic (ceftazidime) against Pseudomonas aeruginosa clinical isolates from cystic fibrosis sputum, greater clearance of biofilms formed from these isolates and in vivo efficacy in a mouse model of respiratory P. aeruginosa infection.

Discovery of ‘all-in-one’ nitric oxide-donor cephalosporin-3′-diazeniumdiolates with dual-antibacterial and antibiofilm properties

2019 Fall National Meeting

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