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

Cephalosporin-NO-donor prodrug PYRRO-C3D shows β-lactam-mediated activity against Streptococcus pneumoniae biofilms
Cephalosporin-NO-donor prodrug PYRRO-C3D shows β-lactam-mediated activity against Streptococcus pneumoniae biofilms
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.
Streptococcus pneumoniae;
1089-8603
Allan, Raymond
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Kelso, Michael J.
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Rineh, Ardeshir
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Yepuri, Nageshwar R.
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Feelisch, Martin
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Soren, Odel
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Brito-Mutunayagam, Sanjita
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Salib, Rami
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Stoodley, Paul
08614665-92a9-4466-806e-20c6daeb483f
Clarke, Stuart C.
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Webb, Jeremy
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Hall-Stoodley, Luanne
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Faust, Saul
f97df780-9f9b-418e-b349-7adf63e150c1
Allan, Raymond
390a7d0a-38e1-410a-8dfe-c8ef8408f5e1
Kelso, Michael J.
6afd2b75-c893-44cf-8b86-93e89e21f894
Rineh, Ardeshir
9b3b5d87-023c-49a3-9290-c793e4fa07c2
Yepuri, Nageshwar R.
74fb7761-9b7e-43ec-b5df-274c2458eb78
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Soren, Odel
fbec1ab5-90ed-4515-a164-b374b0930a26
Brito-Mutunayagam, Sanjita
d2cb1a32-d940-45dd-86f3-b04398ce5044
Salib, Rami
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Stoodley, Paul
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Clarke, Stuart C.
6a26cdfc-8fee-456f-a5ae-9c16db5545b0
Webb, Jeremy
7d2a2c36-ebb8-477e-b08e-e81c49d21532
Hall-Stoodley, Luanne
94ebdc00-b549-4488-b15f-5310fb965f5b
Faust, Saul
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Allan, Raymond, Kelso, Michael J., Rineh, Ardeshir, Yepuri, Nageshwar R., Feelisch, Martin, Soren, Odel, Brito-Mutunayagam, Sanjita, Salib, Rami, Stoodley, Paul, Clarke, Stuart C., Webb, Jeremy, Hall-Stoodley, Luanne and Faust, Saul (2017) Cephalosporin-NO-donor prodrug PYRRO-C3D shows β-lactam-mediated activity against Streptococcus pneumoniae biofilms. Nitric Oxide. (doi:10.1016/j.niox.2017.02.006).

Record type: Article

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.

Text Allan et al. (2017) - Accepted Manuscript
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Accepted/In Press date: 16 February 2017
e-pub ahead of print date: 21 February 2017
Keywords: Streptococcus pneumoniae;
Organisations: nCATS Group, Centre for Biological Sciences, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 406412
URI: https://eprints.soton.ac.uk/id/eprint/406412
ISSN: 1089-8603
PURE UUID: 9bf9903e-f46f-4e2e-ac8c-7ca03cbbd98b
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158
ORCID for Rami Salib: ORCID iD orcid.org/0000-0002-6753-7844
ORCID for Saul Faust: ORCID iD orcid.org/0000-0003-3410-7642

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Date deposited: 10 Mar 2017 10:46
Last modified: 06 Jun 2018 12:47

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Contributors

Author: Raymond Allan
Author: Michael J. Kelso
Author: Ardeshir Rineh
Author: Nageshwar R. Yepuri
Author: Martin Feelisch ORCID iD
Author: Odel Soren
Author: Sanjita Brito-Mutunayagam
Author: Rami Salib ORCID iD
Author: Paul Stoodley
Author: Stuart C. Clarke
Author: Jeremy Webb
Author: Luanne Hall-Stoodley
Author: Saul Faust ORCID iD

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