Mechanisms of action and resistance to miltefosine in Leishmania spp.

• Grant number: 12/14629-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2012
• End date: September 30, 2015
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Silvia Reni Bortolin Uliana
• Grantee: Adriano Cappellazzo Coelho
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Leishmania spp. are parasitic protozoa responsible for a complex of diseases known as leishmaniasis. The treatment of all clinical forms of leishmaniasis relies on costly parenteral administered drugs with multiple undesirable effects. The main drugs available for the treatment of leishmaniasis in Brazil are pentavalent antimony, anfotericin B and pentamidine. Clinical failure after treatment with antimony has been increasingly reported. Recently, the effectiveness of miltefosine in the treatment of visceral leishmaniasis was described and the drug is currently in use mainly for visceral leishmaniasis in Asia and Europe. However, the knowledge about miltefosine's mechanisms of action and resistance and the cellular targets in the parasite is limited. New World Leishmania species are known to be less sensitive to miltefosine than Old World parasites but data on in vitro sensitivity of Leishmania isolates from Brazilian patients is not available. In this project we propose to evaluate the sensitivity of field isolates from Brazil to miltefosine. Based on previous studies, we also intend to characterize a putative phospholipid transporter that is found only in the L. (V.) braziliensis genome and not in other Leishmania species and to generate miltefosine resistant mutants of the Leishmania species endemic in Brazil, aiming to identify potential genes associated to the mechanism of drug resistance. Our study will contribute in the evaluation of miltefosine's potential to be included in the chemotherapeutic arsenal in Brazil and will contribute in the understanding of the mechanisms of action and resistance for this drug and in the identification of potential molecular markers related to miltefosine resistance in Leishmania spp. from Brazil.

Scientific publications

(13)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ESPADA, CAROLINE R.; RIBEIRO-DIAS, FATIMA; DORTA, MIRIAM L.; DE ARAUJO PEREIRA, LEDICE INACIA; DE CARVALHO, EDGAR M.; MACHADO, PAULO R.; SCHRIEFER, ALBERT; YOKOYAMA-YASUNAKA, JENICER K. U.; COELHO, ADRIANO C.; ULIANA, SILVIA R. B.. Susceptibility to Miltefosine in Brazilian Clinical Isolates of Leishmania (Viannia) braziliensis. American Journal of Tropical Medicine and Hygiene, v. 96, n. 3, p. 656-659, 2017. (15/05130-5, 15/09080-2, 12/14629-5, 11/20484-7)

COELHO, ADRIANO C.; OLIVEIRA, JORDANA C.; ESPADA, CAROLINE R.; REIMAO, JULIANA Q.; TRINCONI, CRISTIANA T.; ULIANA, SILVIA R. B.. A Luciferase-Expressing Leishmania braziliensis Line That Leads to Sustained Skin Lesions in BALB/c Mice and Allows Monitoring of Miltefosine Treatment Outcome. PLoS Neglected Tropical Diseases, v. 10, n. 5, MAY 2016. (15/05130-5, 11/18858-6, 12/14629-5, 15/09080-2, 11/20484-7)

COELHO, ADRIANO C.; TRINCONI, CRISTIANA T.; COSTA, CARLOS H. N.; ULIANA, SILVIA R. B.. In Vitro and In Vivo Miltefosine Susceptibility of a Leishmania amazonensis Isolate from a Patient with Diffuse Cutaneous Leishmaniasis. PLoS Neglected Tropical Diseases, v. 8, n. 7, JUL 2014. (11/20484-7, 12/14629-5, 11/18858-6)

ESPADA, CAROLINE R.; MAGALHAES, RUBENS M.; CRUZ, MARIO C.; MACHADO, PAULO R.; SCHRIEFER, ALBERT; CARVALHO, EDGAR M.; HORNILLOS, VALENTIN; ALVES, JOAO M.; CRUZ, ANGELA K.; COELHO, ADRIANO C.; et al. Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 11, n. SI, p. 139-147, DEC 2019. (15/09080-2, 12/14629-5, 16/23405-4, 11/20484-7)

ULIANA, SILVIA R. B.; TRINCONI, CRISTIANA T.; COELHO, ADRIANO C.. Chemotherapy of leishmaniasis: present challenges. Parasitology, v. 145, n. 4, SI, p. 464-480, APR 2018. (15/09080-2, 12/14629-5, 15/23832-7)

PIRES, ALAUSE DA SILVA; BORGES, ARISSA FELIPE; COELHO, ADRIANO CAPPELLAZZO; DORTA, MIRIAM LEANDRO; LINO JUNIOR, RUY DE SOUZA; DE ARAUJO PEREIRA, LEDICE INACIA; PINTO, SEBASTIAO ALVES; PELLI DE OLIVEIRA, MILTON ADRIANO; DE MATOS, GRAZZIELLE GUIMARAES; ABRAHAMSOHN, ISES A.; et al. Identification and Biological Characterization of Leishmania (Viannia) guyanensis Isolated from a Patient with Tegumentary Leishmaniasis in Goias, a Nonendemic Area for This Species in Brazil. BIOMED RESEARCH INTERNATIONAL, 2015. (12/14629-5)

ESPADA, CAROLINE R.; ORTIZ, PAOLA A.; SHAW, JEFFREY J.; BARRAL, ALDINA M. P.; COSTA, JACKSON M. L.; ULIANA, SILVIA R. B.; COELHO, ADRIANO C.. Identification of Leishmania (Viannia) species and clinical isolates of Leishmania (Leishmania) amazonensis from Brazil using PCR-RFLP of the heat-shock protein 70 gene reveals some unexpected observations. DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE, v. 91, n. 4, p. 312-318, AUG 2018. (15/09080-2, 12/14629-5, 16/23405-4, 11/20484-7)

COELHO, ADRIANO C.; TRINCONI, CRISTIANA T.; SENRA, LUISA; YOKOYAMA-YASUNAKA, JENICER K. U.; ULIANA, SILVIA R. B.. Leishmania is not prone to develop resistance to tamoxifen. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 5, n. 3, p. 77-83, DEC 2015. (11/20484-7, 12/14629-5, 11/18858-6)

TRINCONI, CRISTIANA T.; REIMAO, JULIANA Q.; COELHO, ADRIANO C.; ULIANA, SILVIA R. B.. Efficacy of tamoxifen and miltefosine combined therapy for cutaneous leishmaniasis in the murine model of infection with Leishmania amazonensis. Journal of Antimicrobial Chemotherapy, v. 71, n. 5, p. 1314-1322, MAY 2016. (11/18858-6, 12/14629-5, 15/09080-2, 11/20484-7, 11/21970-2)

ESPADA, CAROLINE R.; FERREIRA, BIANCA A.; ORTIZ, PAOLA A.; ULIANA, SILVIA R. B.; COELHO, ADRIANO C.. Full nucleotide sequencing of ribosomal DNA internal transcribed spacer of Leishmania species causing cutaneous leishmaniasis in Brazil and its potential for species typing. Acta Tropica, v. 223, NOV 2021. (12/14629-5, 16/23405-4, 16/21171-6, 15/09080-2, 11/20484-7)

ULIANA, SILVIA R. B.; TRINCONI, CRISTIANA T.; COELHO, ADRIANO C.. Chemotherapy of leishmaniasis: present challenges. Parasitology, v. 145, n. 4, p. 17-pg., 2018-04-01. (15/23832-7, 15/09080-2, 12/14629-5)

ESPADA, CAROLINE R.; MAGALHAES, RUBENS M.; CRUZ, MARIO C.; MACHADO, PAULO R.; SCHRIEFER, ALBERT; CARVALHO, EDGAR M.; HORNILLOS, VALENTIN; ALVES, JOAO M.; CRUZ, ANGELA K.; COELHO, ADRIANO C.; et al. Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 11, p. 9-pg., 2019-12-01. (12/14629-5, 15/09080-2, 11/20484-7, 16/23405-4)

PIRES, ALAUSE DA SILVA; BORGES, ARISSA FELIPE; COELHO, ADRIANO CAPPELLAZZO; DORTA, MIRIAM LEANDRO; LINO JUNIOR, RUY DE SOUZA; DE ARAUJO PEREIRA, LEDICE INACIA; PINTO, SEBASTIAO ALVES; PELLI DE OLIVEIRA, MILTON ADRIANO; DE MATOS, GRAZZIELLE GUIMARAES; ABRAHAMSOHN, ISES A.; et al. Identification and Biological Characterization of Leishmania (Viannia) guyanensis Isolated from a Patient with Tegumentary Leishmaniasis in Goias, a Nonendemic Area for This Species in Brazil. BIOMED RESEARCH INTERNATIONAL, v. 2015, p. 11-pg., 2015-01-01. (12/14629-5)