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Small molecules with antimicrobial activity against E. coli and P. aeruginosa identified by high‐throughput screening
Author(s) -
La Fuente R,
Sonawane N D,
Arumainayagam D,
Verkman A S
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706873
Subject(s) - antimicrobial , antibacterial activity , high throughput screening , antibiotics , escherichia coli , bacteria , potency , microbiology and biotechnology , phenotypic screening , bacterial growth , antibacterial agent , biology , chemistry , pharmacology , in vitro , biochemistry , phenotype , genetics , gene
Background and purpose: New antimicrobials are needed because of the emergence of organisms that are resistant to available antimicrobials. The purpose of this study was to evaluate a high‐throughput screening approach to identify antibacterials against two common disease‐causing bacteria, and to determine the frequency, novelty, and potency of compounds with antibacterial activity. Experimental approach: A high‐throughput, turbidometric assay of bacterial growth in a 96‐well plate format was used to screen a diverse collection of 150,000 small molecules for antibacterial activity against E. coli and P. aeruginosa . The statistical Z′‐factor for the assay was 0.7. Key results: Screening for inhibition of E. coli growth gave a ‘hit’ rate (>60% inhibition at 12.5 μM) of 0.025%, which was more than 5‐fold reduced for P. aeruginosa . The most potent antibacterials (EC 50 <0.5 μM) were of the nitrofuran class followed by naphthalimide, salicylanilide, bipyridinium and quinoazolinediamine chemical classes. Screening of >250 analogs of the most potent antibacterial classes established structure‐activity data sets. Conclusions and Implications: Our results validate and demonstrate the utility of a growth‐based phenotype screen for rapid identification of small‐molecule antibacterials. The favourable efficacy and structure‐activity data for several of the antibacterial classes suggests their potential development for clinical use. British Journal of Pharmacology (2006) 149 , 551–559. doi: 10.1038/sj.bjp.0706873