Active transcriptome remodeling underlies antimony-induced drug tolerance in persister-like Leishmania parasites
- 1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas, United States of America
- 2Department of Biological Sciences, Texas Tech University, Lubbock, Texas, United States of America
Abstract
Persistence - characterized by the transient ability of subpopulations of Leishmania parasites to survive exposure to drugs - is a major driver of treatment failure and clinical relapses in leishmaniasis. Persisters are characterized by non-dividing or slow-growing state and increased drug tolerance. However, the molecular mechanisms governing formation of persisters remain poorly understood in Leishmania parasites. Here, we developed a model to explore persistence in Leishmania mexicana. Viable promastigote persister-like subpopulations were enriched using Ficoll density gradient centrifugation following lethal exposure to potassium antimonyl tartrate (PAT) that killed 80% of parasites. The surviving parasites exhibited delayed growth in drug-free medium that is characteristic for persisters, and higher drug tolerance upon rechallenge. Transcriptomic profiling across acute stress, drug-free recovery, and rechallenge phases revealed a global remodeling in persister-like cells under all tested conditions. Induction was characterized by downregulation of several biological processes and a robust upregulation of nucleolar pathways, supporting epitranscriptomic changes during the formation of persister-like cells. Upon drug removal, this profile rapidly reverted, initiating ribosome biogenesis to exit latency and resume proliferation. Resuscitation phase exhibited active protein synthesis and upregulation in biological processes associated with metabolic and mitochondrial functions. Furthermore, persister-like parasites displayed distinct drug response profiles compared to parental parasites by rapidly implementing a highly conserved, coordinated survival reprogramming, where 316 genes were uniquely downregulated, and 241 genes were upregulated. The distinct features of the drug response in rechallenged persister-like cells were characterized by the downregulation of mitochondrial function and protein synthesis to induce dormant state, and the upregulation of drug-response and stress-tolerance genes to survive immediate toxicity. In contrast, parental parasites displayed a broad and disorganized drug response. Additionally, rechallenged persisters exhibited distinct transcriptomic features that transiently phenocopies stable genetic resistance. This pre-adapted state is characterized by the targeted upregulation of epigenetic and epitranscriptomic modulators, heavy metal transporters, and catabolic enzymes to maintain viability. These findings demonstrate that drug persistence in Leishmania is not merely a metabolic collapse, but rather a sophisticated survival strategy involving active transcriptome remodeling, downregulation of translation and epigenetic/epitranscriptomic changes. This transient state constitutes an initial evolutionary step toward permanent drug resistance and highlights new molecular vulnerabilities for therapeutic interventions aimed at preventing clinical relapse. Author summary: The efficacy of leishmaniasis chemotherapy often fails because Leishmania parasites survive the drugs by entering a dormant state, causing relapses in patients. In this study, however, we discovered that these parasites are not simply ‘quiescent.’ On the contrary, they orchestrate a highly active survival response: they shut down energy-consuming functions while keeping their cellular alert mechanisms active. Remarkably, upon re-exposure to antileishmanial drugs, the parasites recall previous stress events and transiently activate defensive pathways characteristic of stable drug resistance. Understanding how Leishmania employs this temporary adaptive strategy provides critical targets for developing therapies designed to eradicate the infection and avert relapses.
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BibTeX
@article{quiceno2026active,
title = {{Active transcriptome remodeling underlies antimony-induced drug tolerance in persister-like Leishmania parasites}},
author = {Eyson Quiceno and Cristian Camilo Rodríguez-Almonacid and Khalid Omeir and Jacob Ancira and Caleb Phillips and Zemfira N. Karamysheva},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014682},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014682},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Active transcriptome remodeling underlies antimony-induced drug tolerance in persister-like Leishmania parasites
AU - Eyson Quiceno
AU - Cristian Camilo Rodríguez-Almonacid
AU - Khalid Omeir
AU - Jacob Ancira
AU - Caleb Phillips
AU - Zemfira N. Karamysheva
PY - 2026
DA - 2026/10/05
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014682
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014682
AB - Persistence - characterized by the transient ability of subpopulations of Leishmania parasites to survive exposure to drugs - is a major driver of treatment failure and clinical relapses in leishmaniasis. Persisters are characterized by non-dividing or slow-growing state and increased drug tolerance. However, the molecular mechanisms governing formation of persisters remain poorly understood in Leishmania parasites. Here, we developed a model to explore persistence in Leishmania mexicana. Viable promastigote persister-like subpopulations were enriched using Ficoll density gradient centrifugation following lethal exposure to potassium antimonyl tartrate (PAT) that killed 80% of parasites. The surviving parasites exhibited delayed growth in drug-free medium that is characteristic for persisters, and higher drug tolerance upon rechallenge. Transcriptomic profiling across acute stress, drug-free recovery, and rechallenge phases revealed a global remodeling in persister-like cells under all tested conditions. Induction was characterized by downregulation of several biological processes and a robust upregulation of nucleolar pathways, supporting epitranscriptomic changes during the formation of persister-like cells. Upon drug removal, this profile rapidly reverted, initiating ribosome biogenesis to exit latency and resume proliferation. Resuscitation phase exhibited active protein synthesis and upregulation in biological processes associated with metabolic and mitochondrial functions. Furthermore, persister-like parasites displayed distinct drug response profiles compared to parental parasites by rapidly implementing a highly conserved, coordinated survival reprogramming, where 316 genes were uniquely downregulated, and 241 genes were upregulated. The distinct features of the drug response in rechallenged persister-like cells were characterized by the downregulation of mitochondrial function and protein synthesis to induce dormant state, and the upregulation of drug-response and stress-tolerance genes to survive immediate toxicity. In contrast, parental parasites displayed a broad and disorganized drug response. Additionally, rechallenged persisters exhibited distinct transcriptomic features that transiently phenocopies stable genetic resistance. This pre-adapted state is characterized by the targeted upregulation of epigenetic and epitranscriptomic modulators, heavy metal transporters, and catabolic enzymes to maintain viability. These findings demonstrate that drug persistence in Leishmania is not merely a metabolic collapse, but rather a sophisticated survival strategy involving active transcriptome remodeling, downregulation of translation and epigenetic/epitranscriptomic changes. This transient state constitutes an initial evolutionary step toward permanent drug resistance and highlights new molecular vulnerabilities for therapeutic interventions aimed at preventing clinical relapse. Author summary: The efficacy of leishmaniasis chemotherapy often fails because Leishmania parasites survive the drugs by entering a dormant state, causing relapses in patients. In this study, however, we discovered that these parasites are not simply ‘quiescent.’ On the contrary, they orchestrate a highly active survival response: they shut down energy-consuming functions while keeping their cellular alert mechanisms active. Remarkably, upon re-exposure to antileishmanial drugs, the parasites recall previous stress events and transiently activate defensive pathways characteristic of stable drug resistance. Understanding how Leishmania employs this temporary adaptive strategy provides critical targets for developing therapies designed to eradicate the infection and avert relapses.
SN - 1553-7374
ER -