5TVJ

Crystal structure of acetyltransferase Eis from Mycobacterium tuberculosis in complex with CoA and inhibitor 2k*: 1-(4-fluorophenyl)-2-[2-(4-methylphenyl)-2-oxoethyl]pyrrolo[1,2-a]pyrazin-2-ium

Summary for 5TVJ

• Entry DOI: 10.2210/pdb5tvj/pdb
• Descriptor: Enhanced intracellular survival protein, COENZYME A, 1-(4-fluorophenyl)-2-[2-(4-methylphenyl)-2-oxoethyl]pyrrolo[1,2-a]pyrazin-2-ium, ... (6 entities in total)
• Functional Keywords: transferase, acetyltransferase, resistance, aminoglycoside, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 47239.58

Authors

Gajadeera, C.S.,Garzan, A.,Hou, C.,Garneau-Tsodikova, S.,Tsodikov, O.V. (deposition date: 2016-11-09, release date: 2017-03-01, Last modification date: 2023-10-04)

Primary citation

Garzan, A.,Willby, M.J.,Ngo, H.X.,Gajadeera, C.S.,Green, K.D.,Holbrook, S.Y.,Hou, C.,Posey, J.E.,Tsodikov, O.V.,Garneau-Tsodikova, S.
Combating Enhanced Intracellular Survival (Eis)-Mediated Kanamycin Resistance of Mycobacterium tuberculosis by Novel Pyrrolo[1,5-a]pyrazine-Based Eis Inhibitors.
ACS Infect Dis, 3:302-309, 2017

PubMed Abstract: Tuberculosis (TB) remains one of the leading causes of mortality worldwide. Hence, the identification of highly effective antitubercular drugs with novel modes of action is crucial. In this paper, we report the discovery and development of pyrrolo[1,5-a]pyrazine-based analogues as highly potent inhibitors of the Mycobacterium tuberculosis (Mtb) acetyltransferase enhanced intracellular survival (Eis), whose up-regulation causes clinically observed resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN). We performed a structure-activity relationship (SAR) study to optimize these compounds as potent Eis inhibitors both against purified enzyme and in mycobacterial cells. A crystal structure of Eis in complex with one of the most potent inhibitors reveals that the compound is bound to Eis in the AG binding pocket, serving as the structural basis for the SAR. These Eis inhibitors have no observed cytotoxicity to mammalian cells and are promising leads for the development of innovative AG adjuvant therapies against drug-resistant TB.

PubMed: 28192916
DOI: 10.1021/acsinfecdis.6b00193

Experimental method

X-RAY DIFFRACTION (2.3 Å)