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

Shaw, C. D. et al. (2019) Genomic and metabolomic polymorphism among experimentally selected paromomycin-resistant Leishmania donovani strains. Antimicrobial Agents and Chemotherapy, 64(1), e00904-19. (doi: 10.1128/AAC.00904-19) (PMID:31658971) (PMCID:PMC7187574)

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 (PMMr) was induced in three Nepalese clinical strains of Leishmania donovani with different inherent susceptibilities to antimony (Sb) drugs by stepwise 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 50% inhibitory concentration (IC50) values for PMMr parasites varied between 104 and 481 μM at the promastigote stage and 32 and 195 μM at the intracellular amastigote stage. PMM resistance was associated with increased resistance to nitric oxide at the amastigote stage but not the promastigote stage (P < 0.05). This effect was most marked in the Sb-resistant (Sbr) PMMr clone, in which PMM resistance was associated with a significant upregulation of glutathione compared to that in its wild type (P < 0.05), although there was no change in the regulation of trypanothione (detected in its oxidized form). Interestingly, PMMr strains showed an increase in either the keto acid derivative of isoleucine (Sb intermediate PMMr) or the 2-hydroxy acids derived from arginine and tyrosine (Sb susceptible PMMr and Sbr PMMr). These results are consistent with the recent finding that the upregulation of the branched-chain amino acid aminotransferase and d-lactate dehydrogenase is linked to PMMr. In addition, we found that PMMr is associated with a significant increase in aneuploidy during PMM selection in all the strains, which could allow the rapid selection of genetic changes that confer a survival advantage.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cotton, Professor James
• Authors: Shaw, C. D., Imamura, H., Downing, T., Blackburn, G., Westrop, G. D., Cotton, J. A., Berriman, M., Sanders, M., Rijal, S., Coombs, G. H., Dujardin, J. C., and Carter, K. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• Journal Name: Antimicrobial Agents and Chemotherapy
• Publisher: American Society for Microbiology
• ISSN: 0066-4804
• ISSN (Online): 1098-6596
• Copyright Holders: Copyright © 2019 Shaw et al.
• First Published: First published in Antimicrobial Agents and Chemotherapy 64(1): e00904-19
• Publisher Policy: Reproduced under a Creative Commons License
• Data DOI: 10.15129/88f47c26-ff93-4a7c-8c17-d323aa24052e