Open AccessDistinguishing On-Target versus Off-Target Activity in Early Antibacterial Drug Discovery Using a Macromolecular Synthesis Assay
Author(s) -
Mark L. Cunningham,
Bryan P. Kwan,
Kirk Nelson,
Daniel C. Bensen,
Karen Joy Shaw
Publication year - 2013
Publication title -
slas discovery
Language(s) - English
Resource type - Journals
eISSN - 2472-5560
pISSN - 2472-5552
DOI - 10.1177/1087057113487208
Subject(s) - dna gyrase , ciprofloxacin , rifampicin , kanamycin , minimum inhibitory concentration , novobiocin , chloramphenicol , chemistry , drug , antimicrobial , microbiology and biotechnology , biology , pharmacology , antibiotics , escherichia coli , biochemistry , gene
The macromolecular synthesis assay was optimized in both S. aureus and E. coli imp and used to define patterns of inhibition of DNA, RNA, protein, and cell wall biosynthesis of several drug classes. The concentration of drug required to elicit pathway inhibition differed among the antimicrobial agents tested, with inhibition detected at concentrations significantly below the minimum inhibitory concentration (MIC) for tedizolid; within 4-fold of the MIC for ciprofloxacin, cefepime, vancomycin, tetracycline, and chloramphenicol; and significantly above the MIC for rifampicin and kanamycin. In a DNA gyrase/topoisomerase IV structure-based drug design optimization program, the assay rapidly identified undesirable off-target activity within certain chemotypes, altering the course of the program to focus on the series that maintained on-target activity.