Details

Autor(en) / Beteiligte

• Pang, Allan H.
• Green, Keith D.
• Chandrika, Nishad Thamban
• Garzan, Atefeh
• Punetha, Ankita
• Holbrook, Selina Y.L.
• Willby, Melisa J.
• Posey, James E.
• Tsodikov, Oleg V.
• Garneau-Tsodikova, Sylvie

Titel

Discovery of substituted benzyloxy-benzylamine inhibitors of acetyltransferase Eis and their anti-mycobacterial activity

Ist Teil von

• European journal of medicinal chemistry, 2022-11, Vol.242, p.114698, Article 114698

Ort / Verlag

Elsevier Masson SAS

Erscheinungsjahr

2022

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 ∼ 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 mc2 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. A new structural family of Eis inhibitors was discovered to inhibit growth of mycobacteria, but not other bacterial strains, by a separate mechanism of action. [Display omitted] •Inhibitors of acetyltransferase Eis that can act by another mechanism were found.•Novel benzyloxy-benzylamines can act as anti-mycobacterial agents.•Eis inhibitors characterized by biochemical, biophysical, and biological studies.