Discovery of antimicrobial agent targeting tryptophan synthase

Bosken, Yuliana K., Ai, Rizi, Hilario, Eduardo, Ghosh, Rittik K., Dunn, Michael F., Kan, Shih-Hsin, Niks, Dimitri, Zhou, Huanbin, Ma, Wenbo, Mueller, Leonard J., Fan, Li and Chang, Chia-En A. (2022) Discovery of antimicrobial agent targeting tryptophan synthase. Protein Science, 31 (2). pp. 432-442. ISSN 0961-8368

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Antibiotic resistance is a continually growing challenge in the treatment of various bacterial infections worldwide. New drugs and new drug targets are necessary to curb the threat of infectious diseases caused by multidrug-resistant pathogens. The tryptophan biosynthesis pathway is essential for bacterial growth but is absent in higher animals and humans. Drugs that can inhibit the bacterial biosynthesis of tryptophan offer a new class of antibiotics. In this work, we combined a structure-based strategy using in silico docking screening and molecular dynamics (MD) simulations to identify compounds targeting the α subunit of tryptophan synthase with experimental methods involving the whole-cell minimum inhibitory concentration (MIC) test, solution state NMR, and crystallography to confirm the inhibition of L-tryptophan biosynthesis. Screening 1,800 compounds from the National Cancer Institute Diversity Set I against α subunit revealed 28 compounds for experimental validation; four of the 28 hit compounds showed promising activity in MIC testing. We performed solution state NMR experiments to demonstrate that a one successful inhibitor, 3-amino-3-imino-2-phenyldiazenylpropanamide (Compound 1) binds to the α subunit. We also report a crystal structure of Salmonella enterica serotype Typhimurium tryptophan synthase in complex with Compound 1 which revealed a binding site at the αβ interface of the dimeric enzyme. MD simulations were carried out to examine two binding sites for the compound. Our results show that this small molecule inhibitor could be a promising lead for future drug development.

Item Type: Article
Additional Information: Funding Information: This study was supported by the US National Institutes of Health (GM137008, GM109045, and GM097569) and NSF (CHE1710671, and National Supercomputer Centers TG‐CHE130009). The authors would like to thank VeraChem LLC for providing the free Vdock license for academic use.
Uncontrolled Keywords: antimicrobial agents,computer-aided drug discovery,crystal structure,enzyme inhibitor,essential bacterial pathway,molecular docking,structure-based drug discovery,virtual screening,biochemistry,molecular biology,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300/1303
Faculty \ School: Faculty of Science > The Sainsbury Laboratory
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Depositing User: LivePure Connector
Date Deposited: 13 Oct 2022 10:39
Last Modified: 21 Jul 2024 02:31
DOI: 10.1002/pro.4236

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