ArticleAntimicrobial agents and chemotherapy2015
Experimental resistance to drug combinations in Leishmania donovani: metabolic and phenotypic adaptations.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 49 citations in OpenAlex.
- Unravelling drug resistance in leishmaniasis: genomic adaptations and emerging therapies.Frontiers in molecular biosciences · 2025Review
- Comparison of freeze-thaw and sonication cycle-based methods for extracting AMR-associated metabolites fromFrontiers in microbiology · 2023Article
- Four layer multi-omics reveals molecular responses to aneuploidy in Leishmania.PLoS pathogens · 2022Article
- Impact of Genetic Diversity and Genome Plasticity ofFrontiers in cellular and infection microbiology · 2022Review
- Metabolite Biomarkers ofCells · 2021Article
- A Novel Bioimpedance-Based Detection of Miltefosine Susceptibility Among ClinicalFrontiers in cellular and infection microbiology · 2021Article
- Treatment failure to sodium stibogluconate in cutaneous leishmaniasis: A challenge to infection control and disease elimination.PloS one · 2021Article
- Experimental Strategies to Explore Drug Action and Resistance in Kinetoplastid Parasites.Microorganisms · 2020Review
- Comparative mitochondrial proteomics of Leishmania tropica clinical isolates resistant and sensitive to meglumine antimoniate.Parasitology research · 2020Article
- Genomic and Metabolomic Polymorphism among Experimentally Selected Paromomycin-Resistant Leishmania donovani Strains.Antimicrobial agents and chemotherapy · 2019Article
- A BONCAT-iTRAQ method enables temporally resolved quantitative profiling of newly synthesised proteins in Leishmania mexicana parasites during starvation.PLoS neglected tropical diseases · 2019Article
- Chemogenomic Profiling of Antileishmanial Efficacy and Resistance in the Related Kinetoplastid Parasite Trypanosoma brucei.Antimicrobial agents and chemotherapy · 2019Article
- Therapeutic Interventions for Countering Leishmaniasis and Chagas's Disease: From Traditional Sources to Nanotechnological Systems.Pathogens (Basel, Switzerland) · 2019Review
- Untargeted metabolomics to understand the basis of phenotypic differences in amphotericin B-resistantWellcome open research · 2019Article
- Genomic and transcriptomic alterations in Leishmania donovani lines experimentally resistant to antileishmanial drugs.International journal for parasitology. Drugs and drug resistance · 2018Article
- Synergistic combination of alkylphosphocholines with peptaibols in targeting Leishmania infantum in vitro.International journal for parasitology. Drugs and drug resistance · 2018Article
- Integrated genomic and metabolomic profiling of ISC1, an emerging Leishmania donovani population in the Indian subcontinent.Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases · 2018Article
- Molecular Preadaptation to Antimony Resistance in Leishmania donovani on the Indian Subcontinent.mSphere · 2018Article
- Drug resistance and treatment failure in leishmaniasis: A 21st century challenge.PLoS neglected tropical diseases · 2017Review
- Induction of allopurinol resistance in Leishmania infantum isolated from dogs.PLoS neglected tropical diseases · 2017Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Together with vector control, chemotherapy is an essential tool for the control of visceral leishmaniasis (VL), but its efficacy is jeopardized by growing resistance and treatment failure against first-line drugs. To delay the emergence of resistance, the use of drug combinations of existing antileishmanial agents has been tested systematically in clinical trials for the treatment of visceral leishmaniasis (VL). In vitro, Leishmania donovani promastigotes are able to develop experimental resistance to several combinations of different antileishmanial drugs after 10 weeks of drug pressure. Using an untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics approach, we identified metabolic changes in lines that were experimentally resistant to drug combinations and their respective single-resistant lines. This highlighted both collective metabolic changes (found in all combination therapy-resistant [CTR] lines) and specific ones (found in certain CTR lines). We demonstrated that single-resistant and CTR parasite cell lines show distinct metabolic adaptations, which all converge on the same defensive mechanisms that were experimentally validated: protection against drug-induced and external oxidative stress and changes in membrane fluidity. The membrane fluidity changes were accompanied by changes in drug uptake only in the lines that were resistant against drug combinations with antimonials, and surprisingly, drug accumulation was higher in these lines. Together, these results highlight the importance and the central role of protection against oxidative stress in the different resistant lines. Ultimately, these phenotypic changes might interfere with the mode of action of all drugs that are currently used for the treatment of VL and should be taken into account in drug development.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.