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Genetic and chemical knockdown: a complementary strategy for evaluating an anti-infective target

Authors Ramachandran V, Singh R, Yang X, Tunduguru R, Mohapatra S, Khandelwal S, Patel S, Datta S

Received 15 October 2012

Accepted for publication 21 November 2012

Published 7 February 2013 Volume 2013:6 Pages 1—13


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Vasanthi Ramachandran,1,* Ragini Singh,2,* Xiaoyu Yang,1 Ragadeepthi Tunduguru,1 Subrat Mohapatra,2 Swati Khandelwal,2 Sanjana Patel,2 Santanu Datta2

1AstraZeneca India R&D, Bangalore, India; 2Cellworks India, Bangalore, India

*These authors contributed equally to this work

Abstract: The equity of a drug target is principally evaluated by its genetic vulnerability with tools ranging from antisense- and microRNA-driven knockdowns to induced expression of the target protein. In order to upgrade the process of antibacterial target identification and discern its most effective type of inhibition, an in silico toolbox that evaluates its genetic and chemical vulnerability leading either to stasis or cidal outcome was constructed and validated. By precise simulation and careful experimentation using enolpyruvyl shikimate-3-phosphate synthase and its specific inhibitor glyphosate, it was shown that genetic knockdown is distinct from chemical knockdown. It was also observed that depending on the particular mechanism of inhibition, viz competitive, uncompetitive, and noncompetitive, the antimicrobial potency of an inhibitor could be orders of magnitude different. Susceptibility of Escherichia coli to glyphosate and the lack of it in Mycobacterium tuberculosis could be predicted by the in silico platform. Finally, as predicted and simulated in the in silico platform, the translation of growth inhibition to a cidal effect was able to be demonstrated experimentally by altering the carbon source from sorbitol to glucose.

Keywords: knockdown, inhibition, in silico, vulnerability

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