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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Cell. Infect. Microbiol. | doi: 10.3389/fcimb.2019.00251

The inhibitory effect of GlmU acetyltransferase inhibitor TPSA on Mycobacterium tuberculosis may be affected due to its methylation by methyltransferase Rv0560c

  • 1Dalian Medical University, China

Mycobacterium tuberculosis bifunctional enzyme GlmU is a novel target for anti-TB drugs, which involved in glycosyl donor UDP-N-acetylglucosamine biosynthesis. Here, we found that TPSA (2-[5-(2-{[4-(2-thienyl)-2-pyrimidinyl]sulfanyl}acetyl)-2-thienyl]acetic acid) was a novel inhibitor for GlmU acetyltransferase activity (IC50: 5.3 μM). The interaction sites of GlmU and TPSA by molecular docking were confirmed by site-directed mutagenesis. TPSA showed inhibitory effect on Mtb H37Ra growth and intracellular H37Ra in macrophage cells (MIC: 66.5 μM). To investigate why TPSA at higher concentration (66.5 μM) was able to inhibit H37Ra growth, proteome and transcriptome of H37Ra treated with TPSA were analyzed. The expression of two methyltransferases MRA_0565 (Rv0558) and MRA_0567 (Rv0560c) were markedly increased. TPSA was pre-incubated with purified Rv0558 and Rv0560c in the presence of S-adenosylmethionine (methyl donor) respectively, resulting in its decreased inhibitory effect of on GlmU acetyltransferase activity. The inhibition of TPSA on growth of H37Ra with overexpressed Rv0558 and Rv0560c was reduced. These implied that methyltransferases could modify TPSA. The methylation of TPSA catalyzed by Rv0560c was subsequently confirmed by LC-MS. Therefore, TPSA as a GlmU acetyltransferase activity inhibitor may offer structural basis for new anti-tuberculosis drugs. TPSA needs to be modified further by some groups to prevent from its methylation by methyltransferases.

Keywords: Mycobacteria tuberculosis, UDP-GlcNAc, GlmU acetyltransferase, inhibitor, Methyltransferases

Received: 11 Mar 2019; Accepted: 27 Jun 2019.

Edited by:

Ricardo Ataide, Burnet Institute, Australia

Reviewed by:

Anil Ojha, Wadsworth Center, United States
Anna Upton, TB Alliance, United States  

Copyright: © 2019 Ma, Chen, Han, Yan, Wang, Jia, Taj and Zhao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Yufang Ma, Dalian Medical University, Dalian, China,