DataSheet_1_Pharmacometabolomics of Meglumine Antimoniate in Patients With Cutaneous Leishmaniasis.xlsx

Control of cutaneous leishmaniasis (CL) in the Americas is dependent on chemotherapy with parenteral pentavalent antimonials. High rates of treatment failure urge the search for predictive and prognostic markers of therapeutic responsiveness. In this study, we aimed to identify biomarkers of therapeutic response during treatment with meglumine antimoniate (MA). We conducted untargeted metabolomic profiling of plasma samples from CL patients (n = 39; 25 who cured and 14 who did not cure), obtained before and at the end of treatment. Exposure to MA induced metabolic perturbations primarily reflecting alteration in long-chain fatty acid β-oxidation and energy production. Allantoin, N-acetylglutamine, taurine, and pyruvate were significantly more abundant in samples from patients who responded to treatment, and were predictive and prognostic of treatment outcome in this patient cohort (AUC > 0.7). In an ex vivo model of infection, allantoin but not taurine enhanced the MA-dependent killing of intracellular Leishmania (Viannia) panamensis. Our results support the participation of metabolites mediating antioxidant and wound healing responses in clinical cure of CL, revealing relationships between metabolism and immune responses in the outcome of antileishmanial treatment.

美洲地区皮肤利什曼病（cutaneous leishmaniasis, CL）的防控依赖肠外给药的五价锑剂化疗。由于治疗失败率居高不下，亟需探寻治疗反应的预测与预后标志物。本研究旨在识别葡甲胺锑（meglumine antimoniate, MA）治疗期间的治疗反应生物标志物。我们对39名CL患者的血浆样本开展了非靶向代谢组学分析，其中25名患者实现治愈，14名未治愈，样本分别采集于治疗前及治疗结束时。暴露于MA可诱导代谢紊乱，主要反映长链脂肪酸β氧化与能量生成的改变。在治疗应答患者的样本中，尿囊素、N-乙酰谷氨酰胺、牛磺酸及丙酮酸的水平显著升高，且在该患者队列中可有效预测与预后治疗结局（AUC > 0.7）。在体外感染模型中，尿囊素（而非牛磺酸）可增强MA依赖的细胞内巴拿马利什曼原虫（Viannia亚属）的杀伤效应。本研究结果证实，介导抗氧化与伤口愈合反应的代谢物参与CL的临床治愈过程，揭示了抗利什曼原虫治疗结局中代谢与免疫反应之间的关联。