抗菌活性
二氢叶酸还原酶
作用机理
生物化学
化学
酶
细菌
抗生素
组合化学
抗菌剂
体外
立体化学
生物
有机化学
遗传学
作者
Zachary W. Boyer,Hannah Kessler,Hannah Brosman,Kirsten J. Ruud,Alan F. Falkowski,Constance Viollet,Christina R. Bourne,Matthew C. O’Reilly
出处
期刊:ACS omega
[American Chemical Society]
日期:2022-10-13
卷期号:7 (42): 37907-37916
被引量:4
标识
DOI:10.1021/acsomega.2c05071
摘要
Antibiotic resistance among bacteria puts immense strain on public health. The discovery of new antibiotics that work through unique mechanisms is one important pillar toward combating this threat of resistance. A functionalized amino dihydropyrimidine was reported to exhibit antibacterial activity via the inhibition of dihydrofolate reductase, an underexploited antibacterial target. Despite this promise, little is known about its structure–activity relationships (SAR) and mechanism of activity. Toward this goal, the aza-Biginelli reaction was optimized to allow for the preparation of focused libraries of functionalized amino dihydropyridines, which in some cases required the use of variable temperature NMR analysis for the conclusive assignment of compound identity and purity. Antibacterial activity was examined using microdilution assays, and compound interactions with dihydrofolate reductase were assessed using antimicrobial synergy studies alongside in vitro enzyme kinetics, differential scanning fluorimetry, and protein crystallography. Clear antibacterial SAR trends were unveiled (MIC values from >64 to 4 μg/mL), indicating that this compound class has promise for future development as an antibacterial agent. Despite this, the in vitro biochemical and biophysical studies performed alongside the synergy assays call the antibacterial mechanism into question, indicating that further studies will be required to fully evaluate the antibacterial potential of this compound class.
科研通智能强力驱动
Strongly Powered by AbleSci AI