5EC4

Crystal structure of acetyltransferase Eis from Mycobacterium tuberculosis in complex with inhibitor 13g and CoA

Summary for 5EC4

• Entry DOI: 10.2210/pdb5ec4/pdb
• Related: 5EBV
• Descriptor: Enhanced intracellular survival protein, COENZYME A, 5-(3-chlorophenyl)-4-methyl-~{N}-(3-morpholin-4-ylpropyl)-1,1-bis(oxidanylidene)-1,2-thiazol-3-amine, ... (4 entities in total)
• Functional Keywords: transferase, aminoglycoside, resistance, tuberculosis, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 47150.54

Authors

Gajadeera, C.S.,Hou, C.,Garneau-Tsodikova, S.,Tsodikov, O.V. (deposition date: 2015-10-20, release date: 2016-03-30, Last modification date: 2024-03-06)

Primary citation

Willby, M.J.,Green, K.D.,Gajadeera, C.S.,Hou, C.,Tsodikov, O.V.,Posey, J.E.,Garneau-Tsodikova, S.
Potent Inhibitors of Acetyltransferase Eis Overcome Kanamycin Resistance in Mycobacterium tuberculosis.
Acs Chem.Biol., 11:1639-1646, 2016

PubMed Abstract: A major cause of tuberculosis (TB) resistance to the aminoglycoside kanamycin (KAN) is the Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. Upregulation of this enzyme is responsible for inactivation of KAN through acetylation of its amino groups. A 123 000-compound high-throughput screen (HTS) yielded several small-molecule Eis inhibitors that share an isothiazole S,S-dioxide heterocyclic core. These were investigated for their structure-activity relationships. Crystal structures of Eis in complex with two potent inhibitors show that these molecules are bound in the conformationally adaptable aminoglycoside binding site of the enzyme, thereby obstructing binding of KAN for acetylation. Importantly, we demonstrate that several Eis inhibitors, when used in combination with KAN against resistant Mtb, efficiently overcome KAN resistance. This approach paves the way toward development of novel combination therapies against aminoglycoside-resistant TB.

PubMed: 27010218
DOI: 10.1021/acschembio.6b00110

Experimental method

X-RAY DIFFRACTION (2.21 Å)