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Ester-prodrugs of ethambutol control its antibacterial activity and provide rapid screening for mycobacterial hydrolase activity.
Larsen, Erik M; Stephens, Dominique C; Clarke, Nathan H; Johnson, R Jeremy.
Afiliação
  • Larsen EM; Department of Chemistry and Biochemistry, Butler University, 4600 Sunset Ave., Indianapolis, IN 46208, USA.
  • Stephens DC; Department of Chemistry and Biochemistry, Butler University, 4600 Sunset Ave., Indianapolis, IN 46208, USA.
  • Clarke NH; Department of Chemistry and Biochemistry, Butler University, 4600 Sunset Ave., Indianapolis, IN 46208, USA.
  • Johnson RJ; Department of Chemistry and Biochemistry, Butler University, 4600 Sunset Ave., Indianapolis, IN 46208, USA. Electronic address: rjjohns1@butler.edu.
Bioorg Med Chem Lett ; 27(19): 4544-4547, 2017 10 01.
Article em En | MEDLINE | ID: mdl-28882482
M. tuberculosis contains an unusually high number of serine hydrolases by proteome percentage compared to other common bacteria or humans. This letter describes a method to probe the global substrate specificity of mycobacterial serine hydrolases with ester-protected prodrugs of ethambutol, a first-line antibiotic treatment for TB. These compounds were synthesized directly from ethambutol using a selective o-acylation to yield products in high yield and purity with minimal workup. A library of derivatives was screened against M. smegmatis, a non-infectious model for M. tuberculosis, which displayed significantly lowered biological activity compared to ethambutol. Incubation with a general serine hydrolase reactivated each derivative to near-ethambutol levels, demonstrating that esterification of ethambutol should provide a simple screen for mycobacterial hydrolase activity.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pró-Fármacos / Inibidores Enzimáticos / Ésteres / Etambutol / Hidrolases / Antibacterianos Tipo de estudo: Diagnostic_studies / Screening_studies Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pró-Fármacos / Inibidores Enzimáticos / Ésteres / Etambutol / Hidrolases / Antibacterianos Tipo de estudo: Diagnostic_studies / Screening_studies Idioma: En Ano de publicação: 2017 Tipo de documento: Article