Translational reprogramming as a driver of antimony-drug resistance in Leishmania

Abstract

Leishmania is a unicellular protozoan that has a limited transcriptional control and mostly uses post-transcriptional regulation of gene expression, although the molecular mechanisms of the process are still poorly understood. Treatments of leishmaniasis, pathologies associated with Leishmania infections, are limited due to drug resistance. Here, we report dramatic differences in mRNA translation in antimony drug-resistant and sensitive strains at the full translatome level. The major differences (2431 differentially translated transcripts) were demonstrated in the absence of the drug pressure supporting that complex preemptive adaptations are needed to efficiently compensate for the loss of biological fitness once they are exposed to the antimony. In contrast, drug-resistant parasites exposed to antimony activated a highly selective translation of only 156 transcripts. This selective mRNA translation is associated with surface protein rearrangement, optimized energy metabolism, amastins upregulation, and improved antioxidant response. We propose a novel model that establishes translational control as a major driver of antimony-resistant phenotypes in Leishmania.

Análisis epidemiológico, genómico y proteómico de Leishmania infantum en Colombia

“…Interestingly, Andrade et al reported a downregulation of processes related to translation in L. infantum Sb-resistant strains, including rRNA processing, ribosome biogenesis, ribonucleoprotein complex, nucleosome assembly, and overall translation (Andrade et al, 2020). Our results are consistent with recent studies on L. tropica antimony-resistant strains, which also revealed a notable increase in proteins linked to translation (Gutierrez Guarnizo et al, 2023). This implies that changes in ribosomal proteins and translation initiation factors could be pivotal in the observed translational alterations, possibly serving as preemptive adaptations to drug exposure.…”

“…Gutierrez Guarnizo et al, 2023). Integrative omics studies are necessary to study this phenomenon since an integrative comprehension.…”

Molecular Mechanisms of Persistence in Protozoan Parasites

“…However, these compounds have a narrow therapeutic window, and resistant Leishmania strains threaten their efficacy. Recently, our group uncovered that antimony drug resistance is established not only through the acquisition of genetic mutations, as shown in earlier studies, but through the reprogramming of translation that coordinates the lipidome and metabolome remodeling to counteract the drug [ 122 , 123 , 124 ]. Miltefosine, paromomycin, and amphotericin B are other compounds used to treat leishmaniasis, but they also have toxicity issues and face resistance challenges [ 125 , 126 ].…”