Untargeted metabolomic analysis of miltefosine action in Leishmania infantum reveals changes to the internal lipid metabolism
Bibliographic record
Abstract
There are many theories as to the mode of action of miltefosine against Leishmania including alterations to the membrane lipid content, induction of apoptosis and modulation of macrophage responses. Here we perform untargeted metabolomics to elucidate the metabolic changes involved in miltefosine action. Over 800 metabolites were detected, 10% of which were significantly altered after 3.75 h. Many of the changes related to an increase in alkane fragment and sugar release. Fragment release is synchronised with reactive oxygen species production, but native membrane phospholipids remain intact. Signs of DNA damage were also detected as were changes to the levels of some thiols and polyamines. After 5 h of miltefosine treatment the cells showed depleted levels of most metabolites, indicating that the cells' outer membrane integrity had become compromised and internal metabolites were escaping upon cell death. In miltefosine resistant cells, the drug was not internalised and the changes to the internal metabolite levels were not seen. In contrast, cells resistant to antimony (SbIII) had similar corresponding alterations to the levels of internal metabolites as wild-type cells. A detailed knowledge of the mode of action of miltefosine will be important to inform the design of combination therapies to combat leishmaniasis, something that the research community should be prioritising in the coming years.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".