8d23

Crystal structure of acetyltransferase Eis from Mycobacterium tuberculosis in complex with inhibitor SGT529

spinqualitylabelsall models 8d23, resolution 2.14Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8d23 is a 1 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.14Å Ligands: GOL, PVU Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function EIS_MYCTU May participate in pathogenesis, possibly by enhancing survival of the bacteria in host macrophages during infection. Publication Abstract from PubMed A clinically significant mechanism of tuberculosis resistance to the aminoglycoside kanamycin (KAN) is its acetylation catalyzed by upregulated Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. In search for inhibitors of Eis, we discovered an inhibitor with a substituted benzyloxy-benzylamine scaffold. A structure-activity relationship study of 38 compounds in this structural family yielded highly potent (IC50 approximately 1 muM) Eis inhibitors, which did not inhibit other acetyltransferases. Crystal structures of Eis in complexes with three of the inhibitors showed that the inhibitors were bound in the aminoglycoside binding site of Eis, consistent with the competitive mode of inhibition, as established by kinetics measurements. When tested in Mtb cultures, two inhibitors (47 and 55) completely abolished resistance to KAN of the highly KAN-resistant strain Mtb mc(2) 6230 K204, likely due to Eis inhibition as a major mechanism. Thirteen of the compounds were toxic even in the absence of KAN to Mtb and other mycobacteria, but not to non-mycobacteria or to mammalian cells. This, yet unidentified mechanism of toxicity, distinct from Eis inhibition, will merit future studies along with further development of these molecules as anti-mycobacterial agents. Discovery of substituted benzyloxy-benzylamine inhibitors of acetyltransferase Eis and their anti-mycobacterial activity.,Pang AH, Green KD, Chandrika NT, Garzan A, Punetha A, Holbrook SYL, Willby MJ, Posey JE, Tsodikov OV, Garneau-Tsodikova S Eur J Med Chem. 2022 Aug 18;242:114698. doi: 10.1016/j.ejmech.2022.114698. PMID:36037791 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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