posted on 2021-07-20, 15:17authored byChristelle Morelle, Angana Mukherjee, Jiabao Zhang, Fereshteh Fani, Anuj Khandelwal, Hélène Gingras, Jocelyn Trottier, Olivier Barbier, Philippe Leprohon, Martin D. Burke, Marc Ouellette
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.