An organogold compound impairs Leishmania amazonensis amastigotes survival and delays lesion progression in murine cutaneous leishmaniasis: Mechanistic insights

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Minori, Karen ; Gadelha, Fernanda R. ; Bonsignore, Riccardo ; Alcantar, Guillermo Moreno ; Fontes, Josielle, V ; Abbehausen, Camilla ; Brioschi, Mariana B. C. ; de Sousa, Lizandra Maia ; Consonni, Silvio R. ; Casini, Angela ; Miguel, Danilo C.

• Document type: Journal article
• Source: Biochemical Pharmacology; v. 232, p. 9-pg., 2024-12-16.

Abstract

Leishmaniasis is one of the most important neglected diseases, classically characterized by three clinical forms that if left untreated can lead to skin lesions, lifelong scarring, or death depending on the parasite species. Unfortunately, treatment is unsatisfactory and the search for an improved therapy has been a priority. Gold compounds have emerged as promising candidates and among them, Au(I)bis-N-heterocyclic carbene (Au (BzTMX)2) has stood out. We have shown that it alters the plasma membrane permeability of Leishmania amazonensis and L. braziliensis, with superior activity for L. amazonensis. Herein, we moved a step forward towards the elucidation of its mechanism of action in L. amazonensis axenic amastigotes in vitro and in vivo. After 24 h incubation, Au(BzTMX)2 induced changes in safranin O uptake, reflecting the ultrastructural changes observed in mitochondria, especially cristae swelling, and oxygen consumption rates. Besides mitochondrial alterations, plasma membrane blebbing and the formation of multilamellar structures were also observed suggesting an autophagy-like process induction. In vivo, Au(BzTMX)2 was capable of delaying lesion progression, decreasing the total ulcerated area and leading to a marked reduction in the parasite burden of infected BALB/c mice. Taking all into consideration, our results give support to the current knowledge of the importance of gold compounds in therapeutics and open new possibilities for leishmaniasis treatment. (AU)

• FAPESP's process: 21/01504-9 - Effects of parity and age on chondrogenesis and osteogenesis of the pubic symphysis in mice: a morphological and molecular approach to potential risk factors for pelvic organ prolapse
• Grantee: Sílvio Roberto Consonni
• Support Opportunities: Regular Research Grants
• FAPESP's process: 22/06410-5 - Metal complexes as specific enzymatic inhibitors for the treatment of Leishmaniasis: cysteine-proteases and trypanothione reductase
• Grantee: Josielle Vieira Fontes
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 22/02618-0 - Design of novel metallodrugs and innovative administration routes for Leishmaniasis treatment
• Grantee: Camilla Abbehausen
• Support Opportunities: Research Grants - Initial Project
• FAPESP's process: 14/21129-4 - The role of fatty acid-binding proteins in the macrophage infection by Leishmania: a potential target for new drugs against leishmaniasis
• Grantee: Danilo Ciccone Miguel
• Support Opportunities: Research Grants - Young Investigators Grants