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

PeerJ

article

Warangkhana Songsungthong¹  Sunisa Prasopporn¹  Louise Bohan¹  Potjanee Srimanote²  Ubolsree Leartsakulpanich¹  Suganya Yongkiettrakul¹ 

[1] Biosensing and Bioprospecting Research Group, National Center for Genetic Engineering and Biotechnology ,(BIOTEC), National Science and Technology Development Agency;Faculty of Allied Health Sciences, Thammasat University

关键词: Streptococcus suis;    Antibiotics;    Antifolate;    Dihydrofolate reductase;    Pathogen Box;    Diaminopyrimidine;    Drug resistant;    Drug discovery;    Screening;    Growth inhibition;   

DOI  :  10.7717/peerj.10743

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

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.

【 授权许可】

CC BY