| Full text | |
| Author(s): |
Velasquez, Angela Maria Arenas
;
Linares, Irwin Alexander Patino
;
Gaspers, Lawrence D.
;
Bartlett, Paula J.
;
Velasques, Jecika M.
;
Netto, Adelino V. G.
;
Thomas, Andrew P.
;
Graminha, Marcia A. S.
Total Authors: 8
|
| Document type: | Journal article |
| Source: | INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE; v. 27, p. 15-pg., 2025-01-01. |
| Abstract | |
Leishmaniasis is a neglected disease that remains with a limited number of drugs available for chemotherapy and has an increased drug resistance that affects treatment outcomes. Metal-based drugs such as cyclopalladated complex [Pd(dmba)(mu-N3)]2 (CP2), a Leishmania topoisomerase IB inhibitor involved in calcium dysregulation and mitochondrial dysfunction of the parasite, had been an alternative to outline the appearance of chemoresistance. To identify new molecular targets and point out possible resistance mechanisms, a CP2-resistant Leishmania amazonensis (LaR) was selected by stepwise exposure to increasing drug pressure until a line capable of growth in 13.3 mu M CP2. LaR IC50 value was 52.4 mu M (4-fold higher than L. amazonensis-wild type, La ). LaR promastigotes were cross-resistant to other DNA topoisomerase I inhibitors (camptothecin) and more susceptible to anti-leishmanial drugs pentamidine and miltefosine. A protective effect on cell viability was observed by pretreating the parasite with Ca2+ channel blockers followed by CP2 in La but not in LaR. Analyses of the cell viability of La and LaR using electron transport chain (ETC) inhibitors demonstrated that La is more sensitive than LaR. The studies of mitochondrial oxygen consumption demonstrated that LaR is less susceptible to complex III (ubiquinol-cytochrome c reductase - CcR) inhibitor, antimycin A (AA). CcR activities of La and LaR were equal for both strains in the absence of CP2 and significantly decreased, 69 % for La and 51 % for LaR, in the presence of CP2. This resistance is attributed to overexpression of CcR, confirmed by the RT-qPCR. CcR inhibition by CP2 leads the parasite to increase the reactive oxygen species (ROS) production, principally in La. Therefore, in this work, we suggested that CcR is the main target of CP2 in the mitochondria, acting to inhibit mitochondria respiratory, and the LaR mutant has increased activity of CcR, which reduces the formation of ROS. (AU) | |
| FAPESP's process: | 16/19289-9 - Characterization of Mechanism of cell death potentially induced by a binuclear antileishmanial cyclopalladated CP2: a contribution to the rational drug development |
| Grantee: | Angela Maria Arenas Velásquez |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| FAPESP's process: | 16/05345-4 - Improving antimicrobial photodynamic therapy for infectious disease associating peptide aurein 1.2 |
| Grantee: | Carla Raquel Fontana |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 20/04415-4 - Therapeutics for leishmaniasis: from screening to the study of mechanisms of action, a contribution to the discovery of new antileishmanial molecules |
| Grantee: | Marcia Aparecida Silva Graminha |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 18/23015-7 - Antimicrobial photodynamic therapy by continuous and switched mode irradiation against Enterococcus faecalis and Cutibacterium acnes |
| Grantee: | Carla Raquel Fontana |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 19/21661-1 - New insight into the mechanism of action of CP2 in Leishmania: analysis of calcium homeostasis and the respiratory chain |
| Grantee: | Angela Maria Arenas Velásquez |
| Support Opportunities: | Scholarships abroad - Research Internship - Post-doctor |
| FAPESP's process: | 17/03552-5 - Leishmaniasis: from screening to the study of mechanisms of action, a contribution to the discovery of new bioactive molecules |
| Grantee: | Marcia Aparecida Silva Graminha |
| Support Opportunities: | Regular Research Grants |