Songsungthong Warangkhana, Prasopporn Sunisa, Bohan Louise, Srimanote Potjanee, Leartsakulpanich Ubolsree, Yongkiettrakul Suganya
Biosensing and Bioprospecting Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand.
Current Address: Department of Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
PeerJ. 2021 Feb 3;9:e10743. doi: 10.7717/peerj.10743. eCollection 2021.
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 . In this study, the open-source Pathogen Box compound library was screened. Thirty hits that effectively inhibited growth at 10 µM were identified. Among the most potent hits, MMV675968 (a diaminoquinazoline analog) was shown to target dihydrofolate reductase (DHFR) via (1) growth inhibition of an surrogate whose growth is dependent on exogenously expressed DHFR and (2) inhibition of in vitro DHFR activity. Thymidine supplement is able to reverse growth inhibition by MMV675968 in both surrogate and , 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 DHFR and growth. MMV675968 and related compounds thus may serve as starting points for developing antibiotics against drug resistant .
是猪的革兰氏阳性细菌病原体，也是一种新出现的人畜共患病原体。它对多种类抗生素的耐药性日益增强。需要新的候选药物及其靶点知识来对抗抗生素耐药性。在本研究中，对开源病原体盒化合物库进行了筛选。鉴定出30种在10µM时有效抑制其生长的活性化合物。在最有效的活性化合物中，MMV675968（一种二氨基喹唑啉类似物）被证明通过（1）对其生长依赖于外源表达二氢叶酸还原酶（DHFR）的替代菌的生长抑制以及（2）对体外DHFR活性的抑制来靶向该菌的二氢叶酸还原酶。胸腺嘧啶核苷补充剂能够逆转MMV675968对替代菌和该菌的生长抑制，表明与胸腺嘧啶核苷相关的途径是MMV675968的主要靶点。将MMV675968与七种代表不同核心结构的DHFR抑制剂进行比较，发现具有长且灵活侧链的双环2,4-二氨基嘧啶在抑制DHFR和该菌生长方面非常有效。因此，MMV675968及相关化合物可能作为开发抗耐药该菌抗生素的起点。
