Genomic_and_metabolomic_polymorphism_among_experimentally_selected_paromomycin_resistant_Leishmania_donovani_strains-sc-5820
Genomic_and_metabolomic_polymorphism_among_experimentally_selected_paromomycin_resistant_Leishmania_donovani_strains
Understanding the mechanism(s) underpinning drug resistance could lead to novel treatments to reverse the increased tolerance of a pathogen.  In this study paromomycin (PMM) resistance (PMM-R) was induced in three Nepalese clinical strains of L. donovani, with different inherent susceptibility to antimony drugs (Sb), by step-wise exposure of promastigotes to PMM. Exposure to PMM resulted in the production of mixed populations of parasites even though a single cloned population was used at the start of selection.  PMM IC50 values for PMM-R parasites varied between 104-481 µM at the promastigotes stage and 32-195 µM at the intracellular amastigotes stage.  PMM resistance was associated with increased resistance to nitric oxide at the amastigote but not the promastigote stage (p < 0.05).  This effect was most marked in the Sb-R PMM-R clone, where PMM-R resistance was associated with a significant upregulation in glutathione compared to its WT (p < 0.05) although there was no change in trypanothione (detected in its oxidised form).  Interestingly, PMM-R strains showed an increase in either the keto acid derivative of isoleucine (Sb-I PMM-R) or the 2-hydroxy acids derived from arginine and tyrosine (Sb-S PMM-R and Sb-R PMM-R).  These results are consistent with the recent finding that upregulation of the branch-chain amino acid aminotransferase and the D-lactate dehydrogenase are linked to PMM-R. In addition, we found that PMM-R was associated with a significant increase in aneuploidy during PMM selection in all the strains, which could allow rapid selection of genetic changes that confer a survival advantage. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
Genomic and metabolomic polymorphism among experimentally selected paromomycin-resistant Leishmania donovani strains