Molecular Preadaptation to Antimony Resistance in Leishmania donovani on the Indian Subcontinent

Abstract

The “antibiotic resistance crisis” is a major challenge for scientists and medical professionals. This steady rise in drug-resistant pathogens also extends to parasitic diseases, with antimony being the first anti-Leishmania drug that fell in the Indian subcontinent (ISC). Leishmaniasis is a major but neglected infectious disease with limited therapeutic options. Therefore, understanding how parasites became resistant to antimonials is of commanding importance. In this study, we experimentally characterized the dynamics of this resistance acquisition and show for the first time that some Leishmania populations of the ISC were preadapted to antimony resistance, likely driven by environmental factors or by drugs used in the 19th century.

Integrated genomic and metabolomic profiling of ISC1, an emerging Leishmania donovani population in the Indian subcontinent

“…A first experimental verification of this hypothesis was made the context of antimony susceptibility showing CG isolates were pre-adapted to antimony while ISC1 ones were not. This particular feature could be linked to the presence of the H-locus amplification in the CG ( Dumetz et al, 2018 ).…”

“…Our earlier study showed that out of all sampled ISC1 isolates, 75% of them came from patients relapsing to miltefosine treatment, vs 50% for the CG strains ( Imamura et al, 2016 ). We have also demonstrated experimentally that ISC1 parasites need more time and molecular changes to develop antimonial (Sb) resistance in vitro than CG strains, which led to the hypothesis of Sb-resistance pre-adaptation of the CG, but not of ICS1 ( Dumetz et al, 2018 ).…”

The absence of C-5 DNA methylation in Leishmania donovani allows DNA enrichment from complex samples

“…qPCRs were run on a LightCycler 480 (Roche) with a SensiMix SYBR No-ROX kit (Bioline); primer sequences available in Supplementary Table S1. Normalisation was performed using two transcripts previously described as stable in promastigotes and amastigotes in Dumetz et al 54 , LdBPK_340035000 and LdBPK_240021200.…”

Introductory Chapter: Leishmaniasis: An Emerging Clinical Syndrome

“…A host of plant extracts or oils and their phytoconstituents (alkaloids, terpenoids, quinones, flavonoids, saponins, phenylpropanoids, flavonoids, lignoids, naphthoquinones, iridoids, and more) have shown promise in vitro and/or in vivo [36][37][38][39][40][41]. In some cases, the leishmanicidal effect is potentiated by immunomodulation [3,42]. Besides plants, secondary metabolites from microorganisms such as fungi [43] and marine organisms have also been reported.…”

“…Despite intensive research, live vaccines are the only effective vaccines till date against CL while none exists for the visceral form that is the most severe of the various clinical forms of leishmaniasis. Moreover, there is an upward trend in development of resistance to most of the currently available drugs [3]. The chemotherapeutic arsenal is associated with need for hospitalization and prolonged periods of treatment, coupled with high toxicity, which limits the application and patient compliance.…”