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Identification and characterization of inhibitors of Haemophilus influenzae acetohydroxyacid synthase

Paper ID Volume ID Publish Year Pages File Format Full-Text
17548 42677 2011 5 PDF Available
Title
Identification and characterization of inhibitors of Haemophilus influenzae acetohydroxyacid synthase
Abstract

Acetohydroxyacid synthase (AHAS), a potential target for antimicrobial agents, catalyzes the first common step in the biosynthesis of branched-chain amino acids. The gene coding for the AHAS catalytic subunit from Haemophilus influenzae (Hi) was cloned, overexpressed in Escherichia coli, and purified. To identify new inhibitory scaffolds, we used a high-throughput screen to test 221 small diverse chemical compounds against Hi-AHAS. Compounds were selected for their ability to inhibit AHAS in vitro. The screen identified 3 compounds, each representing a structural class, as Hi-AHAS inhibitors with an IC50 in the low micromolar range (4.4–14.6 μM). The chemical scaffolds of the three compounds were oxa-1-thia-4-aza-cyclopenta[b]naphthalene (KHG25229), phenyl-2,3-dihydro-isothiazole (KHG25386), and phenyl-pyrrolidine-3-carboxylic acid phenylamide (KHG25056). Further, molecular docking of the two most potent chemicals, KHG25229 and KHG25386, in Hi-AHAS yielded binding energies of −10.41 and −9.21 kcal/mol, respectively. The binding modes were consistent with inhibition mechanisms, as both chemicals oriented outside the active site. As the need for novel antibiotic classes to combat drug resistant bacteria increases, screening compounds that act against Hi-AHAS may assist in the identification of potential new anti-Hi drugs.

Keywords
AHAS, Acetohydroxy acid synthase; Hi, Haemophilus influenzae; BCAAs, branched-chain amino acids; CSU, catalytic subunit; SUs, sulfonylureas; IMs, imidazolinones; TPs, triazolopyrimidinesAHAS; Docking; Haemophilus influenzae; High-throughput screening
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Identification and characterization of inhibitors of Haemophilus influenzae acetohydroxyacid synthase
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Publisher
Database: Elsevier - ScienceDirect
Journal: Enzyme and Microbial Technology - Volume 49, Issue 1, 10 June 2011, Pages 1–5
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us