Ester-prodrugs of ethambutol control its antibacterial activity and provide rapid screening for mycobacterial hydrolase activity

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Larsen, Erik M.¹  Stephens, Dominique C.¹  Clarke, Nathan H.¹  Johnson, R. Jeremy¹ 

[1] Butler Univ, Dept Chem & Biochem, 4600 Sunset Ave, Indianapolis, IN 46208 USA

关键词: Hydrolases;    M. tuberculosis;    Prodrugs;    Antibiotics;    Tuberculosis;    Ethambutol;   

DOI  :  10.1016/j.bmcl.2017.08.057

来源: Elsevier

【 摘 要 】

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. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

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