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A novel bicyclic 2,4-diaminopyrimidine inhibitor of Streptococcus suis dihydrofolate reductase

Streptococcus suis is a Gram-positive bacterial pathogen of pigs and an emerging zoonotic pathogen. It has become increasingly resistant to multiple classes of antibiotics. New drug candidates and knowledge of their targets are needed to combat antibiotic-resistant S. suis. In this study, the open-s...

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Autores principales: Songsungthong, Warangkhana, Prasopporn, Sunisa, Bohan, Louise, Srimanote, Potjanee, Leartsakulpanich, Ubolsree, Yongkiettrakul, Suganya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: PeerJ Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866885/
https://www.ncbi.nlm.nih.gov/pubmed/33604179
http://dx.doi.org/10.7717/peerj.10743
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author Songsungthong, Warangkhana
Prasopporn, Sunisa
Bohan, Louise
Srimanote, Potjanee
Leartsakulpanich, Ubolsree
Yongkiettrakul, Suganya
author_facet Songsungthong, Warangkhana
Prasopporn, Sunisa
Bohan, Louise
Srimanote, Potjanee
Leartsakulpanich, Ubolsree
Yongkiettrakul, Suganya
author_sort Songsungthong, Warangkhana
collection PubMed
description Streptococcus suis is a Gram-positive bacterial pathogen of pigs and an emerging zoonotic pathogen. It has become increasingly resistant to multiple classes of antibiotics. New drug candidates and knowledge of their targets are needed to combat antibiotic-resistant S. suis. In this study, the open-source Pathogen Box compound library was screened. Thirty hits that effectively inhibited S. suis growth at 10 µM were identified. Among the most potent hits, MMV675968 (a diaminoquinazoline analog) was shown to target S. suis dihydrofolate reductase (SsDHFR) via (1) growth inhibition of an E. coli surrogate whose growth is dependent on exogenously expressed SsDHFR and (2) inhibition of in vitro SsDHFR activity. Thymidine supplement is able to reverse growth inhibition by MMV675968 in both E. coli surrogate and S. suis, indicating that a thymidine-related pathway is a major target of MMV675968. Comparison of MMV675968 with seven DHFR inhibitors representing different core structures revealed that bicyclic 2,4-diaminopyrimidines with long and flexible side chains are highly effective in inhibiting SsDHFR and S. suis growth. MMV675968 and related compounds thus may serve as starting points for developing antibiotics against drug resistant S. suis.
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spelling pubmed-78668852021-02-17 A novel bicyclic 2,4-diaminopyrimidine inhibitor of Streptococcus suis dihydrofolate reductase Songsungthong, Warangkhana Prasopporn, Sunisa Bohan, Louise Srimanote, Potjanee Leartsakulpanich, Ubolsree Yongkiettrakul, Suganya PeerJ Microbiology Streptococcus suis is a Gram-positive bacterial pathogen of pigs and an emerging zoonotic pathogen. It has become increasingly resistant to multiple classes of antibiotics. New drug candidates and knowledge of their targets are needed to combat antibiotic-resistant S. suis. In this study, the open-source Pathogen Box compound library was screened. Thirty hits that effectively inhibited S. suis growth at 10 µM were identified. Among the most potent hits, MMV675968 (a diaminoquinazoline analog) was shown to target S. suis dihydrofolate reductase (SsDHFR) via (1) growth inhibition of an E. coli surrogate whose growth is dependent on exogenously expressed SsDHFR and (2) inhibition of in vitro SsDHFR activity. Thymidine supplement is able to reverse growth inhibition by MMV675968 in both E. coli surrogate and S. suis, indicating that a thymidine-related pathway is a major target of MMV675968. Comparison of MMV675968 with seven DHFR inhibitors representing different core structures revealed that bicyclic 2,4-diaminopyrimidines with long and flexible side chains are highly effective in inhibiting SsDHFR and S. suis growth. MMV675968 and related compounds thus may serve as starting points for developing antibiotics against drug resistant S. suis. PeerJ Inc. 2021-02-03 /pmc/articles/PMC7866885/ /pubmed/33604179 http://dx.doi.org/10.7717/peerj.10743 Text en ©2021 Songsungthong et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.
spellingShingle Microbiology
Songsungthong, Warangkhana
Prasopporn, Sunisa
Bohan, Louise
Srimanote, Potjanee
Leartsakulpanich, Ubolsree
Yongkiettrakul, Suganya
A novel bicyclic 2,4-diaminopyrimidine inhibitor of Streptococcus suis dihydrofolate reductase
title A novel bicyclic 2,4-diaminopyrimidine inhibitor of Streptococcus suis dihydrofolate reductase
title_full A novel bicyclic 2,4-diaminopyrimidine inhibitor of Streptococcus suis dihydrofolate reductase
title_fullStr A novel bicyclic 2,4-diaminopyrimidine inhibitor of Streptococcus suis dihydrofolate reductase
title_full_unstemmed A novel bicyclic 2,4-diaminopyrimidine inhibitor of Streptococcus suis dihydrofolate reductase
title_short A novel bicyclic 2,4-diaminopyrimidine inhibitor of Streptococcus suis dihydrofolate reductase
title_sort novel bicyclic 2,4-diaminopyrimidine inhibitor of streptococcus suis dihydrofolate reductase
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866885/
https://www.ncbi.nlm.nih.gov/pubmed/33604179
http://dx.doi.org/10.7717/peerj.10743
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