GlmU inhibitor from the roots of Euphorbia ebracteolata as an anti-tuberculosis agent. Issue 28 (22nd June 2022)

• Record Type: Journal Article
• Authors: Han, Xiuyan; Chen, Changming; Wang, Honglei; Kang, Jian; Yan, Qiulong; Ma, Yufang; Wang, Wenxin; Wu, Shan; Wang, Chao; Ma, Xiaochi
• Is Part Of: RSC advances. Volume 12:Issue 28(2022)
• Page Start: 18266
• Page End: 18273
• Publication Date: 2022-06-22
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d2ra02044k
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : Ebractenoid F was identified to be a GlmU inhibitor from Euphorbia ebracteolata, which could inhibit the cell wall biosynthesis of M. tb H37Ra, along with the biofilm formation. Abstract : At present, the emerging drug-resistance of Mycobacterium tuberculosis ( M. tb ) against existing frontline drugs has prompted the development of novel anti-tuberculosis agents based on new targets. Activity of the bifunctional enzyme, glucosamine-1-phosphate acetyltransferase activity and N -acetylglucosamine-1-phosphate uridyltransferase (GlmU) is essential for biosynthesis of the mycobacterium cell wall components and has been proposed as a potential drug target for therapeutic interventions. On the basis of the high-throughput screening of the GlmU AT inhibitor, an extract of Euphorbia ehracteolata displayed a significant inhibitory effect among 49 tested herbal medicines. Using the bioassay-guided separation, an aromatic diterpenoid ebractenoid F was identified as a GlmU AT inhibitor (IC50 : 4.608 μg mL −1 ). Inhibition kinetics showed that ebractenoid F acted as a competitive inhibitor for substrate acetyl-CoA and an uncompetitive inhibitor for substrate GlcN-1-P. Ala434 was deduced to be the key active residue for the interaction between ebractenoid F and GlmU. Furthermore, ebractenoid F displayed an anti-mycobacterial effect against M. tb H37Ra with a minimal inhibitory concentration (MIC) of 12.5 μg mL −1 along with an inhibitory effect on the formation of biofilm and a synergistic effect with isoniazid against M. tb H37Ra. Above all, a GlmU inhibitor was identified from E. ehracteolata and is proposed to be a potential therapeutic anti-tumberculosis agent.