Comparative transcript expression analysis of miltefosine-sensitive and miltefosine-resistant Leishmania donovani

Leishmania donovani is the causative agent of anthroponotic visceral leishmaniasis in the Indian subcontinent. Oral miltefosine therapy has recently replaced antimonials in endemic areas. However, the drug is at risk of emergence of resistance due to unrestricted use, and, already, there are indications towards decline in treatment efficacy. Hence, understanding the mechanism of miltefosine resistance in the parasite is crucial. We employed genomic microarray analysis to compare the gene expression patterns of miltefosine-resistant and miltefosine-sensitive L. donovani. Three hundred eleven genes, representing ∼3.9% of the total Leishmania genome, belonging to various functional categories including metabolic pathways, transporters, and cellular components, were differentially expressed in miltefosine-resistant parasite. Results in the present study highlighted the probable mechanisms by which the parasite sustains miltefosine pressure including (1) compromised DNA replication/repair mechanism, (2) reduced protein synthesis and degradation, (3) altered energy utilization via increased lipid degradation, (4) increased ABC 1-mediated drug efflux, and (5) increased antioxidant defense mechanism via elevated trypanothione metabolism. The study provided the comprehensive insight into the underlying mechanism of miltefosine resistance in L. donovani that may be useful to design strategies to increase lifespan of this important oral antileishmanial drug.