Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 149, Issue 5, Pages 551-559Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjp.0706873
Keywords
drug discovery; antimicrobial; HTS; cystic fibrosis; diarrhoea; Escherichia coli; Pseudomonas aeruginosa
Categories
Funding
- NEI NIH HHS [R01 EY013574, EY13574] Funding Source: Medline
- NHLBI NIH HHS [HL59198, HL73856, R01 HL073856, R01 HL059198] Funding Source: Medline
- NIBIB NIH HHS [EB00415, R37 EB000415, R01 EB000415] Funding Source: Medline
- NIDDK NIH HHS [P30 DK072517, DK35124, DK72517, R01 DK035124, R37 DK035124] Funding Source: Medline
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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 mu M) of 0.025%, which was more than 5-fold reduced for P. aeruginosa. The most potent antibacterials (EC50 < 0.5 mu M) were of the nitrofuran class followed by naphthalimide, salicylanilide, bipyridinium and quinoazolinediamine chemical classes. Screening of 4250 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.
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