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Functionality of drug efflux pumps in antimonial resistant Leishmania donovani field isolates

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Title Functionality of drug efflux pumps in antimonial resistant Leishmania donovani field isolates
 
Creator Mandal, Goutam
Sarkar, Avijit
Saha, Piu
Singh, Neeloo
Sundar, Shyam
Chatterjee, Mitali
 
Subject Antimony resistance
Axenic amastigotes
Drug efflux pumps
Multidrug resistance protein (MRP)
Multidrug resistant (MDR)
Promastigotes
Visceral leishmaniasis
 
Description 86-92
The recent upsurge of antimony (Sb) resistance is a major impediment to successful chemotherapy of visceral leishmaniasis (VL). Mechanisms involved in antimony resistance have demonstrated an upregulation of drug efflux pumps; however, the biological role drug efflux pumps in clinical isolates remains to be substantiated. Thus, in this study, the functionality of drug efflux pumps was measured in promastigotes and axenic amastigotes isolated from VL patients, who were either Sb-sensitive (AG83, 2001 and MC9) or resistant (NS2, 41 and GE1) using rhodamine123 as a substrate for multidrug resistant (MDR) pumps and calcein as a substrate for multidrug resistance-associated proteins (MRP) respectively; their specificity was confirmed using established blockers. Sb-resistant (Sb-R) isolates accumulated higher amounts of R123, as compared to Sb-sensitive (Sb-S) isolates. Verapamil, a MDR inhibitor failed to alter R123 accumulation, suggesting absence of classical MDR activity. In Sb-R isolates, both promastigotes and axenic amastigotes accumulated significantly lower amounts of calcein than Sb-S isolates and probenecid, an established pan MRP blocker, marginally increased calcein accumulation. Depletion of ATP dramatically increased calcein accumulation primarily in Sb-R isolates, indicating existence of a MRP-like pump, which was more active in Sb-R isolates. In conclusion, our data suggested that overfunctioning of a MRP-like pump contributed towards generation of Sb-R phenotype in L. donovani field isolates.
 
Date 2009-03-05T05:07:29Z
2009-03-05T05:07:29Z
2009-02
 
Type Article
 
Identifier 0301-1208
http://hdl.handle.net/123456789/3322
 
Language en_US
 
Publisher CSIR
 
Source IJBB Vol.46(1) [February 2009]