Re-sensitization of antimony-resistant Leishmania by highly potent SbV-porphyrin through the involvement of ERG6-coding gene
Bibliographic record
Abstract
Leishmaniasis chemotherapy faces significant challenges, including high costs, severe side effects, and the emergence of drug-resistant parasites, demanding global efforts to identify novel antileishmanial agents. Pentavalent antimony (Sb V ), the primary treatment for over 78 years, suffers from reduced efficacy and high toxicity, underscoring the urgent need for alternatives. We have synthesized metalloporphyrins with potent antileishmanial properties, including the Sb V -porphyrin complex (Sb V T4MPP). Sb V T4MPP exhibited high potency against both Sb-sensitive and Sb-resistant Leishmania spp. with IC 50 as low as 0.05 and 0.12 µM, respectively, for amastigotes and promastigotes; 170-fold more effective than Sb V and with a 28–37-fold selectivity index, highlighting the importance of host cells on drug activity. Sterol profiling of L. infantum revealed that Sb V T4MPP ablated ergosterol production while accumulating cholestane-based sterols (e.g., cholesta-5,7,22-trien-3β-ol). Additional sterols appeared exclusively under Sb V T4MPP treatment, accompanied by upregulated erg6 , encoding sterol-C-24 methyltransferase (SMT), a key enzyme in sterol biosynthesis. Overexpression of ERG6 reduced Sb V T4MPP potency, increasing the IC 50 by 2.5-fold, confirming ERG6's role in its mode of action. Disruption of ergosterol biosynthesis was indirectly confirmed through hypoosmotic shock assays, which indicated increased membrane fluidity in Sb V T4MPP-treated Leishmania . In vivo studies revealed a 96 % reduction in parasite load, highlighting Sb V T4MPP’s efficacy in visceral leishmaniasis model. Since ERG6 is absent in mammals, it represents a selective and promising pharmacological target. Our findings position Sb V T4MPP as a novel chemical entity with potent in vitro and in vivo antileishmanial efficacy, providing mechanistic insights and warranting further preclinical investigation as a promising drug candidate for leishmaniasis treatment. • Sb V -porphyrin is highly active against Sb-sensitive and Sb-resistant Leishmania parasites. • Sterol 24-C-methyltransferase encoded by erg6 gene is important to the Sb V -porphyrin mode of action in Leishmania . • In vivo efficacy of Sb V -porphyrin reinforces it as a promising drug candidate to treat leishmaniasis as part of a drug combination scheme.
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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".