L-Asparaginase of Leishmania donovani: Metabolic target and its role in Amphotericin B resistance

Publication date: Available online 28 September 2017 Source:International Journal for Parasitology: Drugs and Drug Resistance Author(s): Jasdeep Singh, Mohd Imran Khan, Shiv Pratap Singh Yadav, Ankit Srivastava, Kislay K. Sinha, Ashish, Pradeep Das, Bishwajit Kundu Emergence of Amphotericin B (AmB) resistant Leishmania donovani has posed major therapeutic challenge against the parasite. Consequently, combination therapy aimed at multiple molecular targets, based on proteome wise network analysis has been recommended. In this regard we had earlier identified and proposed L-asparaginase of Leishmania donovani (LdAI) as a crucial metabolic target. Here we report that both LdAI overexpressing axenic amastigote and promastigote forms of L. donovani survives better when challenged with AmB as compared to wild type strain. Conversely, qRT-PCR analysis showed an upregulation of LdAI in both forms upon AmB treatment. Our data demonstrates the importance of LdAI in imparting immediate protective response to the parasite upon AmB treatment. In the absence of structural and functional information, we modeled LdAI and validated its solution structure through small angle X-ray scattering (SAXS) analysis. We identified its specific inhibitors through ligand and structure-based approach and characterized their effects on enzymatic properties (Km, Vmax, Kcat) of LdAI. We show that in presence of two of the inhibitors L1 and L2, the survival of L. donovani is compromised whereas over...
Source: International Journal for Parasitology: Drugs and Drug Resistance - Category: Parasitology Source Type: research