Well-Tolerated Amphotericin B Derivatives That Effectively Treat Visceral Leishmaniasis

作者：Christelle Morelle, Angana Mukherjee, Jiabao Zhang, Fereshteh Fani, Anuj Khandelwal, Hélène Gingras, Jocelyn Trottier, Olivier Barbier, Philippe Leprohon, Martin D. Burke, Marc Ouellette · 发表于：ACS Infectious Diseases · 年份：2021 · DOI：10.1021/acsinfecdis.1c00245 · 被引用次数：16 · 研究领域：Research on Leishmaniasis Studies、Trypanosoma species research and implications、Synthesis and Biological Evaluation

Chemotherapy against the neglected tropical disease visceral leishmaniasis (VL) is suboptimal with only four licensed drugs. Amphotericin B (AmB), despite its toxicity, remained a second line drug for a long time. However, the demonstration that liposomal AmB is highly effective against VL propelled it, despite its cost, to a first line drug in many countries. While several ongoing efforts are aiming at finding cheaper and stable AmB-formulations, an alternative strategy is the development of less-toxic AmB derivatives. We show here that two less-toxic AmB derivatives with the carboxylate at position 16 of AmB derivatized to a methyl urea (AmB-MU) or amino urea (AmB-AU) are active in vitro against Leishmania donovani, both as free-living parasites as well as their intracellular form. Both less-toxic derivatives, similarly to AmB, target the ergosterol pathway of L. donovani . While the AmB-AU derivative showed female-specific liver toxicity in vivo, the AmB-MU derivative was well-tolerated and more effective than AmB against experimental VL. These studies are an important step for improving AmB-based therapy against a prevalent parasitic disease.