Miltefosine-resistant Leishmania infantum strains with an impaired MT/ROS3 transporter complex retain amphotericin B susceptibility

Mondelaers, Annelies; Hendrickx, Sarah; Bockstal, Lieselotte Van; Maes, Louis; Caljon, Guy

doi:10.1093/jac/dkx407

Cited by 11 publications

(15 citation statements)

References 16 publications

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“…A small degree of variability was observed in the susceptibility to ampB in these isolates but without significance or correlation with the differences in MF susceptibility. Similar findings were described by Mondelaers et al (2018) on MF resistant L. infantum selected in vitro and/or recovered from patients that retained ampB susceptibility.…”

Section: Discussionsupporting

confidence: 86%

Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake

Espada

Magalhães

Cruz

et al. 2019

International Journal for Parasitology: Drugs and Drug Resistan

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In Brazil, cutaneous leishmaniasis is caused predominantly by L. (V.) braziliensis. The few therapeutic drugs available exhibit several limitations, mainly related to drug toxicity and reduced efficacy in some regions. Miltefosine (MF), the only oral drug available for leishmaniasis treatment, is not widely available and has not yet been approved for human use in Brazil. Our group previously reported the existence of differential susceptibility among L. (V.) braziliensis clinical isolates. In this work, we further characterized three of these isolates of L. (V.) braziliensis chosen because they exhibited the lowest and the highest MF half maximal inhibitory concentrations and were therefore considered less tolerant or more tolerant, respectively. Uptake of MF, and also of phosphocholine, were found to be significantly different in more tolerant parasites compared to the less sensitive isolate, which raised the hypothesis of differences in the MF transport complex Miltefosine Transporter (MT)-Ros3. Although some polymorphisms in those genes were found, they did not correlate with the drug susceptibility phenotype. Drug efflux and compartmentalization were similar in the isolates tested, and amphotericin B susceptibility was retained in MF tolerant parasites, suggesting that increased fitness was also not the basis of observed differences. Transcriptomic analysis revealed that Ros3 mRNA levels were upregulated in the sensitive strain compared to the tolerant ones. Increased mRNA abundance in more tolerant isolates was validated by quantitative PCR. Our results suggest that differential gene expression of the MT transporter complex is the basis of the differential susceptibility in these unselected, naturally occurring parasites.

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Section: Discussionsupporting

confidence: 86%

Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake

Espada

Magalhães

Cruz

et al. 2019

International Journal for Parasitology: Drugs and Drug Resistan

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“…Global antibiotic resistance problem has emerged in the treatment of leishmaniasis too, and a number of papers reporting treatment failures are increasing [50]. Anthroponotic transmission is the main cause of drug resistance in Leishmania species.…”

Section: Treatment and Resistance In Humansmentioning

confidence: 99%

An Overview of Leishmaniasis: Historic to Future Perspectives

Güran¹

2019

Vectors and Vector-Borne Zoonotic Diseases

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Human leishmaniasis is a major public health problem with a wide clinical spectrum. Despite there is an epidemiological diversity of the disease, cases mostly occur in the developing countries around the subtropical region, and the incidence is significantly rising. The disease is usually classified into three groups: cutaneous leishmaniasis, mucosal leishmaniasis, and visceral leishmaniasis. But to ensure their survival in different conditions, Leishmania spp. have developed many adaptation mechanisms and can be seen in different clinical forms as well. Herein, an overview of the characteristics of the disease and the parasite, interactions with the host, clinical aspects, and latest developments in the diagnosis and treatment is presented.

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“…Alternative therapeutic agents include miltefosine, which was originally developed as an anticancer drug [ 9 ]. Miltefosine is the first drug used orally for treating VL patients [ 10 , 11 ], but it can cause teratogenicity, and parasite resistance has also been reported [ 12 , 13 ], which also impacts on its clinical use. The development of a prophylactic human vaccine against VL is strongly considered as a non-toxic, safer, and low-cost alternative to control the spread of disease worldwide.…”

Section: Introductionmentioning

confidence: 99%

Liposomal Formulation of ChimeraT, a Multiple T-Cell Epitope-Containing Recombinant Protein, Is a Candidate Vaccine for Human Visceral Leishmaniasis

et al. 2020

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Background: Leishmaniases are neglected diseases caused by infection with Leishmania parasites and there are no human vaccines in use routinely. The purpose of this study was to examine the immunogenicity of ChimeraT, a novel synthetic recombinant vaccine against visceral leishmaniasis (VL), incorporated into a human-compatible liposome formulation. Methods: BALB/c mice were immunized subcutaneously with ChimeraT/liposome vaccine, ChimeraT/saponin adjuvant, or ChimeraT/saline and immune responses examined in vitro and in vivo. Results: Immunization with the ChimeraT/liposome formulation induced a polarized Th1-type response and significant protection against L. infantum infection. ChimeraT/liposome vaccine stimulated significantly high levels of interferon (IFN)-γ, interleukin (IL)-12, and granulocyte macrophage-colony stimulating factor (GM-CSF) cytokines by both CD4 and CD8 T-cells, with correspondingly lower levels of IL-4 and IL-10 cytokines. Induced antibodies were predominantly IgG2a isotype, and homologous antigen-stimulated spleen cells produced significant nitrite as a proxy for nitric oxide (NO). Furthermore, we examined a small number of treated VL patients and found higher levels of circulating anti-ChimeraT protein IgG2 antibodies, compared to IgG1 levels. Conclusions: Overall, the liposomal formulation of ChimeraT induced a protective Th1-type immune response and thus could be considered in future studies as a vaccine candidate against human VL.

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Miltefosine-resistant Leishmania infantum strains with an impaired MT/ROS3 transporter complex retain amphotericin B susceptibility

Abstract: Mutations present in either the MT and/or ROS3 gene are not sufficient to elicit higher tolerance to amphotericin B. Additional synergistic adaptations may be responsible for the miltefosine/amphotericin B cross-resistance described earlier.

Cited by 11 publications

References 16 publications

Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake

Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake

An Overview of Leishmaniasis: Historic to Future Perspectives

Liposomal Formulation of ChimeraT, a Multiple T-Cell Epitope-Containing Recombinant Protein, Is a Candidate Vaccine for Human Visceral Leishmaniasis

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