Paromomycin for the treatment of Tegumentary Leishmaniasis: investigation in vitro, in vivo and in the identification of molecular markers associated with susceptibility and resistance

• Grant number: 16/21171-6
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: February 01, 2018
• End date: September 30, 2023
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Adriano Cappellazzo Coelho
• Grantee: Adriano Cappellazzo Coelho
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Danilo Ciccone Miguel ; João Marcelo Pereira Alves ; José Angelo Lauletta Lindoso ; Paulo Cesar Cotrim ; Silvia Reni Bortolin Uliana
• Associated scholarship(s): 22/06176-2 - Characterization of a Leishmania amazonensis clinical isolate multiresistant to the drugs used in the treatment of leishmaniasis, BP.MS; 21/00171-6 - Functional characterization of a phospholipid transporter of Leishmania braziliensis: possible role in susceptibility to miltefosine, BP.MS; 19/22175-3 - Identification and functional validation of genes associated with susceptibility and resistance to paromomycin in Leishmania spp, BP.DR; + associated scholarships 20/08030-0 - Susceptibility of clinical isolates of Leishmania (Leishmania) amazonensis to antimonials: investigation of the possible correlation between therapeutic failure and resistance in vitro, BP.IC; 20/01948-1 - Evaluation of susceptibility in vitro of clinical and dog isolates of Leishmania spp. to alternative drugs, BP.MS; 19/02717-6 - Investigation of the prevalence of LRV1 virus in clinical isolates of Leishmania (Viannia) spp. from patients with cutaneous leishmaniasis of a reference hospital, BP.IC; 18/03299-0 - Evaluation of the efficacy of paromomycin in the treatment of experimental cutaneous leishmaniasis, BP.MS - associated scholarships

Abstract

Leishmaniasis is a parasitic disease with wide geographic distribution in Brazil with an increased number of cases in urban areas in recent years. The current state of treatment of different clinical forms of Leishmaniasis is one of the critical areas in the management of this disease, since the drugs used require parenteral use, are costly and induce side effects. The available drugs used in Brazil are limited to pentavalent antimony, amphotericin B and pentamidine. In the last years, two drugs have been approved as alternatives to the treatment of Visceral Leishmaniasis in Asia: miltefosine and paromomycin. In this scenario, we propose to evaluate in this study the susceptibility in vitro to paromomycin in clinical isolates of Leishmania spp. from patients of the State of São Paulo and dogs from the city of Embu-Guaçu, as well as its efficacy in vivo in experimental models of infection with species responsible for Tegumentary Leishmaniasis in Brazil. We also propose to characterize molecularly parasites resistant to paromomycin selected in vitro, in order to identify potential genes linked to susceptibility and resistance to paromomycin. Once identified, genes will be functionally validated using strategies of genetic manipulation of the parasite. This study will assess the potential use of paromomycin for the treatment of Leishmaniasis in Brazil and contribute to a better understanding of the mechanism of action and resistance to paromomycin that are not completely understood, despite its high clinical efficacy against Visceral Leishmaniasis. (AU)

Scientific publications

(8)

(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)

BRIOSCHI, MARIANA B. C.; COSER, ELIZABETH M.; COELHO, ADRIANO C.; GADELHA, FERNANDA R.; MIGUEL, DANILO C.. Models for cytotoxicity screening of antileishmanial drugs: what has been done so far?. INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, v. 60, n. 2, p. 11-pg., 2022-08-01. (14/21129-4, 16/21171-6, 19/22175-3)

REIMAO, JULIANA Q.; PEDRO, DEBORA P. PITA; COELHO, ADRIANO C.. The preclinical discovery and development of oral miltefosine for the treatment of visceral leishmaniasis: a case history. EXPERT OPINION ON DRUG DISCOVERY, v. 15, n. 6, MAR 2020. (18/18954-4, 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.; 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)

COSER, ELIZABETH M.; FERREIRA, BIANCA A.; YAMASHIRO-KANASHIRO, EDITE H.; LINDOSO, JOSE ANGELO L.; COELHO, ADRIANO C.. Susceptibility to paromomycin in clinical isolates and reference strains of Leishmania species responsible for tegumentary leishmaniasis in Brazil. Acta Tropica, v. 215, MAR 2021. (16/21171-6, 18/03299-0, 20/01948-1)

REIMAO, JULIANA QUERO; COSER, ELIZABETH MAGIOLO; LEE, MONICA RAN; COELHO, ADRIANO CAPPELLAZZO. Laboratory Diagnosis of Cutaneous and Visceral Leishmaniasis: Current and Future Methods. MICROORGANISMS, v. 8, n. 11, NOV 2020. (16/21171-6, 18/18954-4)

COSER, ELIZABETH M.; FERREIRA, BIANCA A.; BRANCO, NILSON; YAMASHIRO-KANASHIRO, EDITE H.; LINDOSO, JOSE ANGELO L.; COELHO, ADRIANO C.. Activity of paromomycin against Leishmania amazonensis: Direct correlation between susceptibility in vitro and the treatment outcome in vivo. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 14, p. 91-98, DEC 2020. (16/21171-6, 20/01948-1, 18/03299-0)

FERREIRA, BIANCA A.; COSER, ELIZABETH M.; SABORITO, CRISTIELE; YAMASHIRO-KANASHIRO, EDITE H.; COELHO, ADRIANO C.; LINDOSE, JOSE ANGELO L.. In vitro miltefosine and amphotericin B susceptibility of strains and clinical isolates of Leishmania species endemic in Brazil that cause tegumentary leishmaniasis. Experimental Parasitology, v. 246, p. 7-pg., 2023-01-17. (19/02717-6, 16/21171-6, 20/01948-1, 19/22175-3)