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Genomic and metabolomic polymorphism among experimentally selected paromomycin-resistant Leishmania donovani strains

Published on Sep 23, 2019in Antimicrobial Agents and Chemotherapy4.715
· DOI :10.1128/AAC.00904-19
C. D. Shaw2
Estimated H-index: 2
(Strathclyde Institute of Pharmacy and Biomedical Sciences),
Hideo Imamura17
Estimated H-index: 17
+ 9 AuthorsKatharine C. Carter23
Estimated H-index: 23
(Strathclyde Institute of Pharmacy and Biomedical Sciences)
Abstract
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.
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Trypanosoma brucei, as well as Trypanosoma cruzi and more than 20 species of the genus Leishmania, form a group of flagellated protists that threaten human health. These organisms are transmitted by insects that, together with mammals, are their natural hosts. This implies that during their life cycles each of them faces environments with different physical, chemical, biochemical, and biological characteristics. In this work we review how amino acids are obtained from such environments, how they...
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Trichomonas vaginalis and Tritrichomonas foetus are pathogens that parasitise, respectively, human and bovine urogenital tracts causing disease. Using LC-MS, reference metabolomic profiles were obtained for both species and stable isotope labelling with D-[U-13C6] glucose was used to analyse central carbon metabolism. This facilitated a comparison of the metabolic pathways of T. vaginalis and T. foetus, extending earlier targeted biochemical studies. 43 metabolites, whose identities were confirm...
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