Open AccessA novel bicyclic 2,4-diaminopyrimidine inhibitor of Streptococcus suis dihydrofolate reductase
Author(s) -
Warangkhana Songsungthong,
Sunisa Prasopporn,
Louise Bohan,
Potjanee Srimanote,
Ubolsree Leartsakulpanich,
Suganya Yongkiettrakul
Publication year - 2021
Publication title -
peerj
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.927
H-Index - 70
ISSN - 2167-8359
DOI - 10.7717/peerj.10743
Subject(s) - streptococcus suis , dihydrofolate reductase , pathogen , microbiology and biotechnology , antibiotics , biology , growth inhibition , drug resistance , in vitro , enzyme , biochemistry , gene , virulence
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 ( Ss DHFR) via (1) growth inhibition of an E. coli surrogate whose growth is dependent on exogenously expressed Ss DHFR and (2) inhibition of in vitro Ss DHFR 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 Ss DHFR and S. suis growth. MMV675968 and related compounds thus may serve as starting points for developing antibiotics against drug resistant S. suis .