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Ester-prodrugs of ethambutol control its antibacterial activity and provide rapid screening for mycobacterial hydrolase activity
Authors:Erik M. Larsen  Dominique C. Stephens  Nathan H. Clarke  R. Jeremy Johnson
Affiliation:Department of Chemistry and Biochemistry, Butler University, 4600 Sunset Ave., Indianapolis, IN 46208, USA
Abstract: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.
Keywords:Hydrolases  Prodrugs  Antibiotics  Tuberculosis  Ethambutol
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