Mycobacterium ulcerans is the causative agent of Buruli ulcer, a debilitating chronic disease that mainly affects the skin. Current treatments for Buruli ulcer are efficacious, but rely on the use of antibiotics with severe side effects. The enzyme dihydrofolate reductase (DHFR) plays a critical role in the de novo biosynthesis of folate species and is a validated target for several antimicrobials. Here we describe the biochemical and structural characterization of M. ulcerans DHFR and identified P218, a safe antifolate compound in clinical evaluation for malaria, as a potent inhibitor of this enzyme. We expect our results to advance M. ulcerans DHFR as a target for future structure-based drug discovery campaigns.

中文翻译：

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鉴定 P218 作为溃疡分枝杆菌 DHFR 的有效抑制剂

溃疡分枝杆菌是布鲁里溃疡的病原体，布鲁里溃疡是一种主要影响皮肤的使人衰弱的慢性疾病。目前对布鲁里溃疡的治疗是有效的，但依赖于具有严重副作用的抗生素的使用。二氢叶酸还原酶 (DHFR) 在叶酸物种的从头生物合成中起关键作用，并且是几种抗菌剂的有效靶标。在这里，我们描述了溃疡分枝杆菌DHFR的生化和结构特征，并确定了 P218（一种用于疟疾临床评估的安全抗叶酸化合物）作为该酶的有效抑制剂。我们希望我们的结果推动溃疡分枝杆菌DHFR 作为未来基于结构的药物发现活动的目标。