ArticleACS infectious diseases2018
Potent 1,2,4-Triazino[5,6 b]indole-3-thioether Inhibitors of the Kanamycin Resistance Enzyme Eis from Mycobacterium tuberculosis.
Article in ACS infectious diseases, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 26 citations in OpenAlex.
- Targeting RNA-Binding Oncofetal Protein IGF2BP3: Discovery of Potent and Selective Inhibitors.Journal of medicinal chemistry · 2026Article
- NProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Restoring susceptibility to aminoglycosides: identifying small molecule inhibitors of enzymatic inactivation.RSC medicinal chemistry · 2023Review
- Discovery and Mechanistic Analysis of Structurally Diverse Inhibitors of Acetyltransferase Eis among FDA-Approved Drugs.Biochemistry · 2023Article
- Discovery and development of inhibitors of acetyltransferase Eis to combat Mycobacterium tuberculosis.Methods in enzymology · 2023Article
- Discovery of substituted benzyloxy-benzylamine inhibitors of acetyltransferase Eis and their anti-mycobacterial activity.European journal of medicinal chemistry · 2022Article
- An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis.Molecules (Basel, Switzerland) · 2021Review
- Structure-based design of haloperidol analogues as inhibitors of acetyltransferase Eis fromRSC medicinal chemistry · 2021Article
- Structure-Guided Optimization of Inhibitors of Acetyltransferase Eis fromACS chemical biology · 2020Article
- Small-Molecule Acetylation by GCN5-RelatedMicrobiology and molecular biology reviews : MMBR · 2020Review
- Article
- Probing the Robustness of Inhibitors of Tuberculosis Aminoglycoside Resistance Enzyme Eis by Mutagenesis.ACS infectious diseases · 2019Article
- Peptidoglycan pathways: there are still more!RSC advances · 2019Review
- Mutation and Transmission Profiles of Second-Line Drug Resistance in Clinical Isolates of Drug-ResistantFrontiers in microbiology · 2019Article
- Mycobacterial Aminoglycoside Acetyltransferases: A Little of Drug Resistance, and a Lot of Other Roles.Frontiers in microbiology · 2019Article
- The Role of Antibiotic-Target-Modifying and Antibiotic-Modifying Enzymes inFrontiers in microbiology · 2018Review
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
A common cause of resistance to kanamycin (KAN) in tuberculosis is overexpression of the enhanced intracellular survival (Eis) protein. Eis is an acetyltransferase that multiacetylates KAN and other aminoglycosides, rendering them unable to bind the bacterial ribosome. By high-throughput screening, a series of substituted 1,2,4-triazino[5,6 b]indole-3-thioether molecules were identified as effective Eis inhibitors. Herein, we purchased 17 and synthesized 22 new compounds, evaluated their potency, and characterized their steady-state kinetics. Four inhibitors were found not only to inhibit Eis in vitro, but also to act as adjuvants of KAN and partially restore KAN sensitivity in a Mycobacterium tuberculosis KAN-resistant strain in which Eis is upregulated. A crystal structure of Eis in complex with a potent inhibitor and CoA shows that the inhibitors bind in the aminoglycoside binding site snugly inserted into a hydrophobic cavity. These inhibitors will undergo preclinical development as novel KAN adjuvant therapies to treat KAN-resistant tuberculosis.
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Registered trials
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