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Meglumine antimoniate is the first-line drug against all forms of Leishmaniasis in Iran.Unfortunately,the incidence rate of drug-resistant cutaneous Leishmaniasis unresponsive to meglumine antimoniate is increasing in Iranian patients.In order to define the protein expressional changes related to the process of drug resistance in anthroponotic cutaneous leishmaniasis (ACL),we performed a comparative proteomics analysis on promastigotes of two genetically related Leishmania tropica clinical field isolates.Meglumine antimoniate sensitive and resistant L.tropica isolated from ACL patients in northeastern Iran.Whole cell proteins of cultured promastigotes were analyzed with 2-DE and differentially expressed proteins were further identified by MALDI-Tof-Tof mass spectrometry.Activated protein kinase c receptor (LACK),protein disulfide isomerase,and iron superoxide dismutase were those proteins with over-expression profile in drug resistant isolate.Alpha tubulin,prostaglandin f2-alpha synthase,and vesicular transport protein were down-expressed in drug resistant promastigotes.This proteomics analysis provided possible molecular mechanisms in drug resistance of Iranian L.tropica isolates.We discussed the cellular function of these proteins and their probable roles in drug resistance.Altered expression of these proteins and the biochemical pathways they are involved in are the interesting subjects to be further examined in order to determine and confirm their correlation with drug resistance in L.tropica.