Distinguishing on-target versus off-target activity in early antibacterial drug discovery using a macromolecular synthesis assay.
J Biomol Screen
; 18(9): 1018-26, 2013 Oct.
Article
em En
| MEDLINE
| ID: mdl-23686103
ABSTRACT
The macromolecular synthesis assay was optimized in both S. aureus and E. coli imp and used to define patterns of inhibition of DNA, RNA, protein, and cell wall biosynthesis of several drug classes. The concentration of drug required to elicit pathway inhibition differed among the antimicrobial agents tested, with inhibition detected at concentrations significantly below the minimum inhibitory concentration (MIC) for tedizolid; within 4-fold of the MIC for ciprofloxacin, cefepime, vancomycin, tetracycline, and chloramphenicol; and significantly above the MIC for rifampicin and kanamycin. In a DNA gyrase/topoisomerase IV structure-based drug design optimization program, the assay rapidly identified undesirable off-target activity within certain chemotypes, altering the course of the program to focus on the series that maintained on-target activity.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
3_ND
Base de dados:
MEDLINE
Assunto principal:
Staphylococcus aureus
/
Bioensaio
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Escherichia coli
/
Antibacterianos
Idioma:
En
Revista:
J Biomol Screen
Ano de publicação:
2013
Tipo de documento:
Article