Well-Tolerated Amphotericin B Derivatives That Effectively Treat Visceral Leishmaniasis

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.

In Vitro Drug Susceptibility of a Leishmania (Leishmania) infantum Isolate from a Visceral Leishmaniasis Pediatric Patient after Multiple Relapses

“…The amastigote form of the ME isolate was similarly susceptible to SbV, AmB deoxycholate, and MF as the LD strain, with no significant difference in the EC 50 values ( Table 1 ), despite the patient being refractory to these treatments [ 17 ]. Differently, laboratory-selected SbV- and AmB-resistant L. (L.) infantum and L. (L.) donovani lines exhibit a minimum of a 3-fold increase in EC 50 values, reaching more than a 10-fold increase when compared with their corresponding parental strains [ 28 , 29 , 30 , 31 , 32 ]. Finally, the LD strain and the ME isolate were also uniformly susceptible to PEN and PM ( Table 1 ).…”

In silico and in vitro potentials of crocin and amphotericin B on Leishmania major: Multiple synergistic mechanisms of actions

“…AmpB is a polyene macrolide used to treat leishmaniasis among various conventional formulations. The discerning activity of this antibiotic against Leishmania species is due to its superior affinity targeting ergosterols biosynthesis, which is more principal in the plasma membrane of these parasites than the cholesterol existing in the mammalian cell membranes [24]. Combining different drugs with various mechanistic actions can provide potential synergism, hence exerting a more significant therapeutic effect in treating disease, and this signifies the most promising approach for developing novel leishmanicidal preparations [25].…”

Investigação da suscetibilidade à anfotericina B e à miltefosina em isolados clínicos de "Leishmania" spp.

“…Além do aumento dos níveis de ALT, foi observado também que a partir do terceiro dia de tratamento, nos grupos tratados com as concentrações de 5 e 10 mg/kg/dia, que os animais começaram apresentarar o pêlo eriçado, sinal associado a dor e desconforto e que pode estar relacionado à toxicidade do fármaco (Neves, 2013). estruturais em genes associados a biossíntese de ergosterol (Mbongo et al 1998, Bansal et al 2019, Ning et al 2020, Morelle et al 2021, o principal esterol de membrana de tripanossomatídeos (Goad et al 1984, Urbina 1997). Em um estudo realizado por Mbongo et al (1998) por exemplo, foi selecionada uma linhagem resistente in vitro à AmB na forma promastigota de L. (L.) donovani.…”

“…Além da alteração nos níveis de ALT, foi também observado nos grupos tratados com 5 e 10 mg/kg/dia de AmB que a partir do terceiro dia de tratamento, os animais apresentaram pêlo eriçado. Em um estudo realizado por Morelle et al (2021), foi comparada a atividade in vivo da AmB convencional e três de seus derivados (AmBisome, AmB amino-ureia e AmB metil-ureia) em animais infectados com L. (L.) donovani.…”

“…O estudo demonstrou que tanto a AmB, como seus derivados não apresentaram toxicidade renal. No entanto, a AmB amino-ureia nas concentrações de 4 e 8 mg/kg exibiu toxicidade hepática, com aumento dos níveis séricos da enzima ALT (Morelle et al 2021).…”