Ester-prodrugs of ethambutol control its antibacterial activity and provide rapid screening for mycobacterial hydrolase activity
| Autor: | Dominique Stephens, R. Jeremy Johnson, Nathan H. Clarke, Erik M. Larsen |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.drug_class Hydrolases 030106 microbiology Clinical Biochemistry Antibiotics Mycobacterium smegmatis Drug Evaluation Preclinical Pharmaceutical Science Microbial Sensitivity Tests Biochemistry Article Microbiology Serine 03 medical and health sciences Structure-Activity Relationship Drug Discovery medicine Prodrugs Enzyme Inhibitors Molecular Biology Ethambutol biology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Biological activity Serine hydrolase Esters Mycobacterium tuberculosis Prodrug biology.organism_classification bacterial infections and mycoses Anti-Bacterial Agents 030104 developmental biology Molecular Medicine Antibacterial activity Bacteria medicine.drug |
| Zdroj: | Bioorganicmedicinal chemistry letters. 27(19) |
| ISSN: | 1464-3405 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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