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.
Highlights
The use of drug combinations, either in co-formulations or coadministrations, is an established approach for the treatment of several infectious diseases including malaria and tuberculosis [1]
Resistance could be induced in Leishmania if this approach is not applied in a controlled and regulated way, resulting in a rapid loss of efficacy of not one but two therapeutic options
We have designed relevant experimental studies in order to determine whether Leishmania parasites are able to develop resistance to the different potential anti-leishmanial drug combinations that will be used in the near future
Summary
The use of drug combinations, either in co-formulations or coadministrations, is an established approach for the treatment of several infectious diseases including malaria and tuberculosis [1]. This approach has recently become a priority for other tropical parasitic diseases, such as visceral leishmaniasis [2,3,4,5,6]. Chemotherapy is the only current treatment option for leishmaniasis, its efficacy is increasingly limited by growing resistance to first-line drugs, especially antimonials, the frequent side-effects associated with their use, and the high cost of treatment [7,8]. The recommended first-line therapies for 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 [9]; ii) the polyene antibiotic amphotericin B (AmB); iii) the liposomal formulation AmBisome; iv) the aminoglycoside paromomycin (PMM); and v) the oral drug miltefosine (MLF)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
