Susceptibility to miltefosine in Leishmania (Viannia) braziliensis clinical isolates: phenotypic characterization and investigation of the basis involved in reduced susceptibility to the drug

• Grant number: 16/23405-4
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: March 01, 2017
• End date: August 31, 2020
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Silvia Reni Bortolin Uliana
• Grantee: Caroline Ricce Espada
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 18/25299-2 - Investigating the role of Ros3 in differential susceptibility of Leishmania to miltefosine using a CRISPR/Cas9 approach, BE.EP.DD

Abstract

Leishmania (Viannia) braziliensis is the main etiological agent of Cutaneous Leishmaniasis in Brazil, where in 2014 approximately 21,000 new cases of the disease were notified. The arsenal available for treatment is limited due to parenteral administration, toxicity, high cost, and emergence of resistance. Miltefosine is the only oral drug approved for the treatment of Cutaneous and Visceral Leishmaniasis and it is in use in Colombia and India. Only two clinical trials evaluating the efficacy of miltefosine for Cutaneous Leishmaniasis in Brazil were performed and in both, miltefosine was more active than pentavalent antimonials. Nevertheless, miltefosine is not yet approved for Leishmaniasis treatment in Brazil and there are no studies on the susceptibility of Brazilian clinical isolates to this drug. Thus, the aim of this project is to evaluate the susceptibility of L. (V.) braziliensis clinical isolates, obtained from patients of two different regions of Brazil, to miltefosine and to elucidate the molecular bases implicated on differential susceptibility to this drug in these isolates. The susceptibility to miltefosine was characterized for 17 L. (V.) braziliensis clinical isolates, never exposed to this drug and we found significant differences in effective drug concentrations among different isolates. In order to understand the molecular basis responsible for the differences on miltefosine susceptibility found between the isolates, the influx, accumulation, distribution and efflux of the drug and the nucleotide sequence and gene expression pattern of the genes encoding the miltefosine transporter (MT) and its subunit Ros3 will be determined. (AU)

Scientific publications

(6)

(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 RICCE; LEVATTI, ERICA V. DE CASTRO; BOITE, MARIANA CORTES; LAMOUNIER, DORCAS; ALVAR, JORGE; CUPOLILLO, ELISA; COSTA, CARLOS HENRIQUE NERY; RODE, JOELLE; ULIANA, SILVIA R. B.. In Vitro Susceptibility to Miltefosine of Leishmania infantum (syn. L. chagasi) Isolates from Different Geographical Areas in Brazil. MICROORGANISMS, v. 9, n. 6, JUN 2021. (16/23405-4)

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)

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)

ESPADA, CAROLINE R.; ALBUQUERQUE-WENDT, ANDREIA; HORNILLOS, VALENTIN; GLUENZ, EVA; COELHO, ADRIANO C.; ULIANA, SILVIA R. B.. Ros3 (Lem3p/CDC50) Gene Dosage Is Implicated in Miltefosine Susceptibility in Leishmania (Viannia) braziliensis Clinical Isolates and in Leishmania (Leishmania) major. ACS INFECTIOUS DISEASES, v. 7, n. 4, p. 849-858, APR 9 2021. (15/09080-2, 18/25299-2, 16/23405-4, 16/21171-6)

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)

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)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

ESPADA, Caroline Ricce. Susceptibility to miltefosine in Leishmania (Viannia) braziliensis clinical isolates: phenotypic characterization and investigation of the basis involved in reduced susceptibility to the drug.. 2020. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.