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

2006/09/18 by R De La Fuente, Ricardo de la Fuente, N.D. Sonawane +5 · 25 citations
Medicine · Chemistry · Computer Science · #Microbial Natural Products and Biosynthesis #Antimicrobial agents and applications #Computational Drug Discovery Methods

paper · pdf · doi:10.1038/sj.bjp.0706873

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 > or = 0.7. KEY RESULTS: Screening for inhibition of E. coli growth gave a 'hit' rate (> 60% inhibition at 12.5 microM) of 0.025%, which was more than 5-fold reduced for P. aeruginosa. The most potent antibacterials (EC50 < 0.5 microM) 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.

Citations

• The millennium bugs — the need for and development of new antibacterials
• Antibiotic Susceptibility Testing by a Standardized Single Disk Method

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