Characterization of natural antimony resistance in Leishmania donovani isolates.
Clinical resistance to pentavalent antimonial compounds has long been recognized as a major problem in the treatment of visceral leishmaniasis in India. However, mechanisms of natural resistance are unclear. In this study, we observed that Leishmania donovani clinical isolates not responsive to sodium stibogluconate showed resistance to antimony treatment in both in vitro and in vivo laboratory conditions. The resistant isolates have increased levels of intracellular thiols. This increase in thiol levels was not mediated by the amplification of gamma-glutamylcysteine synthetase, but was accompanied by amplification of trypanothione reductase and an intracellular ATP-binding cassette transporter gene MRPA. The resistance of parasites to antimony could be reversed by the glutathione biosynthesis-specific inhibitor, buthionine sulfoximine, which resulted in increased drug susceptibility. These results suggest the possible role of thiols and MRPA in antimony resistance in field isolates.
Mittal
Mukul K
MK
Division of Biochemistry, Central Drug Research Institute, Lucknow, India.
Rai
Smita
S
Ashutosh
Ravinder
Gupta
Suman
S
Sundar
Shyam
S
Goyal
Neena
N
D000818:Animals; D000965:Antimony / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002478:Cells, Cultured; D004351:Drug Resistance / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects* / Q000502:physiology; D007898:Leishmaniasis, Visceral / Q000469:parasitology; D013438:Sulfhydryl Compounds / Q000378:metabolism
D000981:Antiprotozoal Agents; D013438:Sulfhydryl Compounds; D019328:Buthionine Sulfoximine; D000965:Antimony