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Amebicidal Effect of Adamantane-Azole Gold(I) Complexes: Cell Death Mechanisms and Synergistic Action with
Gabrieli Eduarda Israel1, Gabriella da Rosa Monte Machado1, Dayara Corrêa Matiola1
1Laboratório de Investigação Aplicada a Protozoários Emergentes (LADIPE), Programa de Pós-Graduação em Farmácia, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
Abstract:
Acanthamoeba spp. are free-living protozoa associated with severe infections such as amebic keratitis and granulomatous amebic encephalitis. The absence of effective treatments highlights the need for new bioactive molecules targeting both trophozoite and cyst forms. This study evaluated the anti-Acanthamoeba activity of adamantane-azole gold-(I) complexes (C1 and C4) and their interaction with thioredoxin reductase (TrxR). Complexes C2, C3, and C4 exhibited potent amoebicidal activity with IC50 values of 0.12, 14, and 6.2 μM, respectively. They disrupted the cell cycle and induced phosphatidylserine exposure, while C4 also triggered mitochondrial depolarization. Ultrastructural alterations, synergy with chlorhexidine, and absence of toxicity in vitro and in vivo models were observed. Molecular docking confirmed TrxR as a potential target. These findings demonstrate the therapeutic promise of C2, C3, and C4 gold-(I) complexes against Acanthamoeba spp. infections, combining potent activity with minimal toxicity and supporting further investigation of their mechanisms of action.
Insights
New gold-(I) complexes show potent activity against Acanthamoeba, a parasite causing severe infections. These compounds effectively target both parasite forms with minimal toxicity, offering promising therapeutic potential.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Parasitology
Background:
- Acanthamoeba species are protozoa responsible for serious human infections like amebic keratitis and granulomatous amebic encephalitis.
- Current treatments for Acanthamoeba infections are limited, necessitating the development of novel therapeutic agents targeting both trophozoite and cyst stages.
Purpose of the Study:
- To evaluate the anti-Acanthamoeba activity of novel adamantane-azole gold-(I) complexes.
- To investigate the mechanism of action, including potential molecular targets like thioredoxin reductase (TrxR).
Main Methods:
- Synthesis and characterization of adamantane-azole gold-(I) complexes.
- In vitro testing of amoebicidal activity against Acanthamoeba trophozoites and cysts.
- Cell cycle disruption, phosphatidylserine exposure, and mitochondrial membrane potential assays.
- Molecular docking studies to identify potential protein targets.
- In vitro and in vivo toxicity assessments.
Main Results:
- Complexes C2, C3, and C4 demonstrated significant amoebicidal activity with low IC50 values (0.12-14 μM).
- These complexes induced cell cycle arrest and phosphatidylserine externalization, with C4 also causing mitochondrial depolarization.
- Ultrastructural damage, synergistic effects with chlorhexidine, and lack of toxicity in host cells and animal models were observed.
- Molecular docking identified thioredoxin reductase (TrxR) as a likely molecular target.
Conclusions:
- Adamantane-azole gold-(I) complexes (C2, C3, C4) exhibit potent anti-Acanthamoeba activity.
- These compounds offer a promising therapeutic strategy for Acanthamoeba infections due to their efficacy and low toxicity.
- Further research into their precise mechanisms of action is warranted.
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