Leishmania donovani Develops Resistance to Drug Combinations

Abstract

Drug combinations for the treatment of leishmaniasis represent a promising and challenging chemotherapeutic strategy that has recently been implemented in different endemic areas. However, the vast majority of studies undertaken to date have ignored the potential risk that Leishmania parasites could develop resistance to the different drugs used in such combinations. As a result, this study was designed to elucidate the ability of Leishmania donovani to develop experimental resistance to anti-leishmanial drug combinations. The induction of resistance to amphotericin B/miltefosine, amphotericin B/paromomycin, amphotericin B/SbIII, miltefosine/paromomycin, and SbIII/paromomycin was determined using a step-wise adaptation process to increasing drug concentrations. Intracellular amastigotes resistant to these drug combinations were obtained from resistant L. donovani promastigote forms, and the thiol and ATP levels and the mitochondrial membrane potential of the resistant lines were analysed. Resistance to drug combinations was obtained after 10 weeks and remained in the intracellular amastigotes. Additionally, this resistance proved to be unstable. More importantly, we observed that promastigotes/amastigotes resistant to one drug combination showed a marked cross-resistant profile to other anti-leishmanial drugs. Additionally, the thiol levels increased in resistant lines that remained protected against the drug-induced loss of ATP and mitochondrial membrane potential. We have therefore demonstrated that different resistance patterns can be obtained in L. donovani depending upon the drug combinations used. Resistance to the combinations miltefosine/paromomycin and SbIII/paromomycin is easily obtained experimentally. These results have been validated in intracellular amastigotes, and have important relevance for ensuring the long-term efficacy of drug combinations.

DNA Repair Pathways in Trypanosomatids: from DNA Repair to Drug Resistance

“…However, resistance should be avoided. For instance, miltefosine-paromomycin and SbIII-paromomycin combinations lead to resistance in Leishmania donovani (291). The combination of therapeutic arsenals to increase treatment efficiency as well as decrease cure duration and drug resistance is for the moment the most satisfactory strategy, since no vaccine against trypanosomatids has been discovered so far.…”

Combination Therapy with Tamoxifen and Amphotericin B in Experimental Cutaneous Leishmaniasis

“…A trial is under way in East Africa to determine the efficacy of miltefosine in combination with SSG and liposomal amphotericin B (7). However, there is concern about the emergence of resistance even for combination therapy (8), since it has been shown that stepwise in vitro selection is an efficient method to obtain resistant lines of Leishmania donovani against all drugs in use today, including amphotericin B (9). Amphotericin B resistance has also been detected in clinical isolates (10).…”

A New ABC Half-Transporter in Leishmania major Is Involved in Resistance to Antimony

“…The recommended first-line therapies for visceral leishmaniasis (VL) include: (i) pentavalent antimonials (meglumine antimoniate and sodium stibogluconate), except in some regions in the Indian subcontinent where there are significant areas of drug resistance (2); (ii) the polyene antibiotic amphotericin B; (iii) the liposomal formulation AmBisome; (iv) the aminoglycoside paromomycin; and (v) the oral drug miltefosine. Although the World Health Organization (WHO) (1,3) recently recommended the use of either a single dose of AmBisome or combinations of antileishmanial drugs in order to reduce the duration and toxicity of treatment, prolong the therapeutic life span of existing drugs and delay the emergence of resistance, recent experimental findings have demonstrated the ability of Leishmania to develop resistance to different drug combinations (4).…”