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.

与其他常见细菌或人类相比，结核分枝杆菌的蛋白质组百分数含有异常高的丝氨酸水解酶数量。这封信描述了一种方法，该方法可通过酯保护的乙胺丁醇的前药（一种用于结核病的一线治疗）来探测分枝杆菌丝氨酸水解酶的整体底物特异性。这些化合物直接从乙胺丁醇使用选择性合成的Ò酰化，得到的产品以高收率和纯度以最小的后处理。筛选了针对耻垢分枝杆菌（一种非传染性结核分枝杆菌模型）的衍生物库与乙胺丁醇相比，其生物活性大大降低。与一般的丝氨酸水解酶一起温育可使每种衍生物重新活化至接近乙胺丁醇的水平，这表明乙胺丁醇的酯化应为分枝杆菌水解酶的活性提供简单的筛选方法。