Proteomic analysis of the soluble proteomes of miltefosine-sensitive and -resistant Leishmania infantum chagasi isolates obtained from Brazilian patients with different treatment outcomes

Abstract

Visceral leishmaniasis (VL) is a serious disease with a challenging treatment plan requiring the prolonged and painful applications of poorly tolerated toxic drugs. Therefore, the identification of miltefosine, an effective and safe oral drug, was considered a significant advancement in leishmaniasis therapy. However, different sensitivities to miltefosine in Leishmania have been observed in clinically relevant species, and the biological mechanism by which clinical isolates of Leishmania acquire drug resistance is poorly understood. Our work aims to elucidate the mechanism of natural resistance to miltefosine in Leishmania by studying the isolates from VL patients who displayed different miltefosine treatment outcomes.

Intracellular amastigote replication may not be required for successful in vitro selection of miltefosine resistance in Leishmania infantum

“…Since both HIV co-infected patients and dogs have difficulties clearing all parasites upon drug treatment, they actually may harbor a huge parasite reservoir under potential continuous drug selection pressure linked to multiple treatment courses, hence facilitating emergence of drug resistance. Most relapse isolates from Brazil where treatment of dogs is not uncommon actually display a decreased MIL-susceptibility (Carnielli et al 2014), in contrast to the Indian L. donovani isolates mentioned earlier. Of particular interest are two laboratory-confirmed MIL-resistant L. infantum isolates isolated from HIV co-infected patients in Europe (Cojean et al 2012;Hendrickx et al 2014).…”

Genomic Appraisal of the Multifactorial Basis for In Vitro Acquisition of Miltefosine Resistance in Leishmania donovani

“…Traditionally, one of the challenges faced by proteomics is attaining a significant detection threshold for changes in membrane-bound proteins that are difficult to resolve by mass spectrometry proteomics, since the technologies are biased toward soluble hydrophilic peptides (64). In fact, of the comparative proteomics studies addressing drug resistance (65)(66)(67)(68), only one stressed the importance of PgP (a membrane glycoprotein) expression as a beacon for HePC resistance, underscoring the importance of complementary omics to acquire the most comprehensive insight for multifaceted processes, such as HePC resistance. In this regard, other complementary proteomic approaches concerning the lines described in this study are in progress.…”

How pH Modulates the Dimer-Decamer Interconversion of 2-Cys Peroxiredoxins from the Prx1 Subfamily

“…Up-regulation of this protein has been associated with protection against apoptosis-like death (26) and resistance to miltefosine (27), a drug whose activity is linked to apoptosis and disturbance of lipiddependent cell signaling pathways (28). Moreover, Leishmania Prx1m confers thermotolerance to the parasite and displays in vitro chaperone activity, which seems to be crucial for virulence (29).…”