Well-Tolerated Amphotericin B Derivatives That Effectively Treat Visceral Leishmaniasis

Christelle Morelle, Angana Mukherjee, Jiabao Zhang, Fereshteh Fani, Anuj Khandelwal, Hélène Gingras, Jocelyn Trottier, Olivier Barbier, Philippe Leprohon, Martin D. Burke, Marc Ouellette

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2472-2482
Number of pages11
JournalACS Infectious Diseases
Volume7
Issue number8
DOIs
StatePublished - Aug 13 2021

Keywords

  • amphotericin
  • Leishmania
  • methyltransferase
  • next-generation sequencing
  • resistance
  • sterols

ASJC Scopus subject areas

  • Infectious Diseases

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