Cephalosporin-NO-donor prodrug PYRRO-C3D shows β-lactam-mediated activity against Streptococcus pneumoniae biofilms

Authors

Raymond Allan, University Hospital Southampton, University of Southampton
Michael J. Kelso, University of WollongongFollow
Ardeshir Rineh, University of WollongongFollow
Nageshwar Rao Yepuri, University of WollongongFollow
Martin Feelisch, University of Southampton, University Hospital Southampton
Odel Soren, University of Southampton
Sanjita Brito-Mutunayagam, University of Southampton
Rami Salib, University Hospital Southampton, University of Southampton
Paul Stoodley, University of Southampton, Ohio State University
Stuart Clarke, University of Southampton, University Hospital Southampton
Jeremy Webb, University of Southampton, University Hospital Southampton
Luanne Hall-Stoodley, University of Southampton, Ohio State University
Saul Faust, University of Southampton, University Hospital Southampton

RIS ID

112833

Publication Details

Allan, R. N., Kelso, M. J., Rineh, A., Yepuri, N. R., Feelisch, M., Soren, O., Brito-Mutunayagam, S., Salib, R. J., Stoodley, P., Clarke, S. C., Webb, J. S., Hall-Stoodley, L. & Faust, S. N. (2017). Cephalosporin-NO-donor prodrug PYRRO-C3D shows β-lactam-mediated activity against Streptococcus pneumoniae biofilms. Nitric Oxide - Biology and Chemistry, 65 43-49.

Abstract

Bacterial biofilms show high tolerance towards antibiotics and are a significant problem in clinical settings where they are a primary cause of chronic infections. Novel therapeutic strategies are needed to improve anti-biofilm efficacy and support reduction in antibiotic use. Treatment with exogenous nitric oxide (NO) has been shown to modulate bacterial signaling and metabolic processes that render biofilms more susceptible to antibiotics. We previously reported on cephalosporin-3'-diazeniumdiolates (C3Ds) as NO-donor prodrugs designed to selectively deliver NO to bacterial infection sites following reaction with β-lactamases. With structures based on cephalosporins, C3Ds could, in principal, also be triggered to release NO following β-lactam cleavage mediated by transpeptidases/penicillin-binding proteins (PBPs), the antibacterial target of cephalosporin antibiotics. Transpeptidase-reactive C3Ds could potentially show both NO-mediated anti-biofilm properties and intrinsic (β-lactam-mediated) antibacterial effects. This dual-activity concept was explored using Streptococcus pneumoniae, a species that lacks β-lactamases but relies on transpeptidases for cell-wall synthesis. Treatment with PYRRO-C3D (a representative C3D containing the diazeniumdiolate NO donor PYRRO-NO) was found to significantly reduce viability of planktonic and biofilm pneumococci, demonstrating that C3Ds can elicit direct, cephalosporin-like antibacterial activity in the absence of β-lactamases. While NO release from PYRRO-C3D in the presence of pneumococci was confirmed, the anti-pneumococcal action of the compound was shown to arise exclusively from the β-lactam component and not through NO-mediated effects. The compound showed similar potency to amoxicillin against S. pneumoniae biofilms and greater efficacy than azithromycin, highlighting the potential of C3Ds as new agents for treating pneumococcal infections.