8D23

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

Summary for 8D23

• Entry DOI: 10.2210/pdb8d23/pdb
• Descriptor: N-acetyltransferase Eis, 1-{2-[(3-chlorophenyl)methoxy]phenyl}-N-[(pyridin-3-yl)methyl]methanamine, GLYCEROL, ... (4 entities in total)
• Functional Keywords: resistance, aminoglycoside, enzyme, inhibitor, acetyl transfer, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 1
• Total formula weight: 46430.04

Authors

Pang, A.H.,Punetha, A.,Garneau-Tsodikova, S.,Tsodikov, O.V. (deposition date: 2022-05-27, release date: 2022-09-14, Last modification date: 2023-10-18)

Primary citation

Pang, A.H.,Green, K.D.,Chandrika, N.T.,Garzan, A.,Punetha, A.,Holbrook, S.Y.L.,Willby, M.J.,Posey, J.E.,Tsodikov, O.V.,Garneau-Tsodikova, S.
Discovery of substituted benzyloxy-benzylamine inhibitors of acetyltransferase Eis and their anti-mycobacterial activity.
Eur.J.Med.Chem., 242:114698-114698, 2022

PubMed Abstract: 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 (IC ∼ 1 μM) 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 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.

PubMed: 36037791
DOI: 10.1016/j.ejmech.2022.114698

Experimental method

X-RAY DIFFRACTION (2.14 Å)