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Metabolite Biomarkers of Leishmania Antimony Resistance.

ABSTRACT: Leishmania parasites cause leishmaniasis, one of the most epidemiologically important neglected tropical diseases. Leishmania exhibits a high ability of developing drug resistance, and drug resistance is one of the main threats to public health, as it is associated with increased incidence, mortality, and healthcare costs. The antimonial drug is the main historically implemented drug for leishmaniasis. Nevertheless, even though antimony resistance has been widely documented, the mechanisms involved are not completely understood. In this study, we aimed to identify potential metabolite biomarkers of antimony resistance that could improve leishmaniasis treatment. Here, using L. tropica promastigotes as the biological model, we showed that the level of response to antimony can be potentially predicted using ¹H-NMR-based metabolomic profiling. Antimony-resistant parasites exhibited differences in metabolite composition at the intracellular and extracellular levels, suggesting that a metabolic remodeling is required to combat the drug. Simple and time-saving exometabolomic analysis can be efficiently used for the differentiation of sensitive and resistant parasites. Our findings suggest that changes in metabolite composition are associated with an optimized response to the osmotic/oxidative stress and a rearrangement of carbon-energy metabolism. The activation of energy metabolism can be linked to the high energy requirement during the antioxidant stress response. We also found that metabolites such as proline and lactate change linearly with the level of resistance to antimony, showing a close relationship with the parasite's efficiency of drug resistance. A list of potential metabolite biomarkers is described and discussed.

SUBMITTER: Gutierrez Guarnizo SA

PROVIDER: S-EPMC8146733 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose: In this study, we have used a translatomic approach by coupling polysome profiling and deep RNA-sequencing to estimate changes in the translatome of antimony-resistant Leishmania parasites Methods: Leishmania tropica promastigotes were stepwise selected for resistance to trivalent antimony. Two different strains were studied, the L. tropica SbIII-sensitive or wildtype strain (WT) and the derived highly resistant strain (HR). After polysome profiling four types of samples were evaluated by deep RNAseq: total mRNA used as input, monosomes (MS), light polysomes (LP), and heavy polysomes (HP). The DESeq2 algorithm was used for differential expression analysis to identify translational changes at the basal level (HR Vs. WT), translational changes to combat the drug (HR+SbIII Vs. HR), and to compare translatomic Vs. transcriptomic changes (HP Vs. Total input) [see overall design section below]. Results: Differential translational analysis (cutoff of fold change ≥ 1.5 and p-value corrected by Benjamini-Hochberg FDR ≤ 0.05) showed that transcripts composition per polysome fraction was different in the resistant strain. It included several upregulated (Up) and downregulated (Down) transcripts. At the basal level, 2431 different transcripts were differentially translated: monosome (Down: 4, Up: 0), light polysomes (Down: 906, Up: 951), and heavy polysomes (Down: 1096, Up: 1064). Under the antimony challenge, 189 different transcripts were differentially translated: monosome (Down: 0, Up: 2), light polysomes (Down: 9, Up: 57), and heavy polysomes (Down: 30, Up: 134). Overall, most of the changes were identified in polysome fraction when compared with monosomes or total transcriptome. Conclusions: Our study shows evidence that translational control has a main role in coordinating the resistance to antimony in Leishmania parasites. We propose a novel model that establishes translational control as a major driver of antimony-resistant phenotypes in Leishmania parasites.

Project description:Antimonials (Sb) were used for decades for chemotherapy of visceral leishmaniasis (VL). Now abandoned in the Indian subcontinent (ISC) because of Leishmania donovani resistance, this drug offers a unique model for understanding drug resistance dynamics. In a previous phylogenomic study, we found two distinct populations of L. donovani: the core group (CG) in the Gangetic plains and ISC1 in the Nepalese highlands. Sb resistance was only encountered within the CG, and a series of potential markers were identified. Here, we analyzed the development of resistance to trivalent antimonials (SbIII) upon experimental selection in ISC1 and CG strains. We observed that (i) baseline SbIII susceptibility of parasites was higher in ISC1 than in the CG, (ii) time to SbIII resistance was higher for ISC1 parasites than for CG strains, and (iii) untargeted genomic and metabolomic analyses revealed molecular changes along the selection process: these were more numerous in ISC1 than in the CG. Altogether these observations led to the hypothesis that CG parasites are preadapted to SbIII resistance. This hypothesis was experimentally confirmed by showing that only wild-type CG strains could survive a direct exposure to the maximal concentration of SbIII The main driver of this preadaptation was shown to be MRPA, a gene involved in SbIII sequestration and amplified in an intrachromosomal amplicon in all CG strains characterized so far. This amplicon emerged around 1850 in the CG, well before the implementation of antimonials for VL chemotherapy, and we discuss here several hypotheses of selective pressure that could have accompanied its emergence.IMPORTANCE The "antibiotic resistance crisis" is a major challenge for scientists and medical professionals. This steady rise in drug-resistant pathogens also extends to parasitic diseases, with antimony being the first anti-Leishmania drug that fell in the Indian subcontinent (ISC). Leishmaniasis is a major but neglected infectious disease with limited therapeutic options. Therefore, understanding how parasites became resistant to antimonials is of commanding importance. In this study, we experimentally characterized the dynamics of this resistance acquisition and show for the first time that some Leishmania populations of the ISC were preadapted to antimony resistance, likely driven by environmental factors or by drugs used in the 19th century.

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Metabolite Biomarkers of Leishmania Antimony Resistance.

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