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


METHODS
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.


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
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.
De La Fuente
R
R
Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0521, USA.
Sonawane
N D
ND
Arumainayagam
D
D
Verkman
A S
AS
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects* / Q000254:growth & development; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D050296:Microbial Viability / Q000187:drug effects; D015394:Molecular Structure; D053644:Naphthalimides / Q000737:chemistry / Q000494:pharmacology; D009391:Nephelometry and Turbidimetry / Q000379:methods; D009581:Nitrofurans / Q000737:chemistry / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology; D015203:Reproducibility of Results; D012458:Salicylanilides / Q000737:chemistry / Q000494:pharmacology
C516671:1,1'-bis(4-methoxyphenyl)-4,4'-bipyridinium; D000900:Anti-Bacterial Agents; D053644:Naphthalimides; D009581:Nitrofurans; D011726:Pyridinium Compounds; D011799:Quinazolines; D012458:Salicylanilides