Identification and functional validation of genes associated with susceptibility and resistance to paromomycin in Leishmania spp

Abstract

Leishmaniasis is a parasitic disease considered neglected by the World Health Organization and that has presented in recent years an increasing number of cases in Brazil, especially in urban regions. The cutaneous form of the disease is caused in Brazil mainly by Leishmania (Leishmania) amazonensis and L. (Viannia) braziliensis, while the visceral form is caused by L. (L.) infantum. The control of Leishmaniasis in Brazil is limited to the use of parenterally administered drugs that induce severe side effects. The drugs used are pentavalent antimonials, amphotericin B and pentamidine. Recently, two drugs have been approved as alternatives to the treatment of visceral Leishmaniasis in Asia: miltefosine and paromomycin. Although not yet approved for the treatment of Leishmaniasis in Brazil, there is great potential for these drugs to be used in the chemotherapy of the disease. In this research project, we propose to identify potential genes associated with susceptibility and resistance to paromomycin through whole genome sequencing of clinical isolates with differential susceptibility to paromomycin and of resistant lines selected in vitro of the main species responsible for tegumentary Leishmaniasis in Brazil. Once identified, genes will be functionally validated through tools of genetic manipulation of the parasite. This study will contribute to a better understanding of the mechanism of action and resistance of paromomycin that are not completely understood in Leishmania, as well as its potential use in chemotherapy of the disease in Brazil. (AU)