8F55

Crystal structure of acetyltransferase Eis from Mycobacterium tuberculosis H37Rv in complex with inhibitor SGT1614

Summary for 8F55

• Entry DOI: 10.2210/pdb8f55/pdb
• Descriptor: N-acetyltransferase Eis, (2E)-2-[(4-chlorophenyl)methylidene]hydrazine-1-carboximidamide, DIMETHYL SULFOXIDE, ... (6 entities in total)
• Functional Keywords: drug resistance, acetylation, histone, inhibition, aminoglycoside, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 1
• Total formula weight: 47125.08

Authors

Pang, A.H.,Punetha, A.,Garneau-Tsodikova, S.,Tsodikov, O.V. (deposition date: 2022-11-11, release date: 2023-02-01, Last modification date: 2023-10-25)

Primary citation

Pang, A.H.,Green, K.D.,Punetha, A.,Thamban Chandrika, N.,Howard, K.C.,Garneau-Tsodikova, S.,Tsodikov, O.V.
Discovery and Mechanistic Analysis of Structurally Diverse Inhibitors of Acetyltransferase Eis among FDA-Approved Drugs.
Biochemistry, 62:710-721, 2023

PubMed Abstract: Over one and a half million people die of tuberculosis (TB) each year. Multidrug-resistant TB infections are especially dangerous, and new drugs are needed to combat them. The high cost and complexity of drug development make repositioning of drugs that are already in clinical use for other indications a potentially time- and money-saving avenue. In this study, we identified among existing drugs five compounds: azelastine, venlafaxine, chloroquine, mefloquine, and proguanil as inhibitors of acetyltransferase Eis from , a causative agent of TB. Eis upregulation is a cause of clinically relevant resistance of TB to kanamycin, which is inactivated by Eis-catalyzed acetylation. Crystal structures of these drugs as well as chlorhexidine in complexes with Eis showed that these inhibitors were bound in the aminoglycoside binding cavity, consistent with their established modes of inhibition with respect to kanamycin. Among three additionally synthesized compounds, a proguanil analogue, designed based on the crystal structure of the Eis-proguanil complex, was 3-fold more potent than proguanil. The crystal structures of these compounds in complexes with Eis explained their inhibitory potencies. These initial efforts in rational drug repositioning can serve as a starting point in further development of Eis inhibitors.

PubMed: 36657084
DOI: 10.1021/acs.biochem.2c00658

Experimental method

X-RAY DIFFRACTION (2.2 Å)