Small molecules with antimicrobial activity against E. coli and P. aeruginosa identified by high-throughput screening

Abstract

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. © 2006 Nature Publishing Group. All rights reserved.