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Evaluation of the antifungal potential of N, N chelating iridium(III) complexes
Cláudia Malta-Luís1, Carolina V Mariano1, Álvaro J Arana2
1Instituto de Tecnologia Química e Biológica António Xavier, Avenida da República, Oeiras, Lisboa, 2780-157, Portugal.
Abstract:
Candida species are opportunistic yeasts and the leading cause of invasive fungal infections in hospitals. These infections are associated with high morbidity and mortality and impose a significant burden on patients and healthcare systems. Their severity is exacerbated by the limited number of effective therapeutics and the growing prevalence of antifungal resistance, underscoring the urgent need for agents with novel mechanisms of action. In this work, we synthesized two half-sandwich iridium(III) complexes with the general formula [Ir(η⁵-Cp*)Cl(N, N)]X, where the N, N-chelating ligand is 1,10-phenanthroline-5,6-dione. The complexes differ only in the counterion (X): triflate for Ir1 and chloride for Ir2. Both complexes exhibited activity against all tested medically relevant fungi; however, their antifungal potency was strongly influenced by the nature of the counterion, with the triflate-containing complex Ir1 displaying superior efficacy and MIC values ranging from 0.3 to 0.5 µM against Candida spp. In vitro, Ir1 outperformed the clinically used antifungals caspofungin and fluconazole and retained activity against fluconazole-resistant strains. Ir1 also inhibited biofilm formation and appears to act, at least in part, by inducing reactive oxygen species (ROS). Remarkably, Ir1 exhibited low in vivo toxicity and effectively treated invasive Candida albicans infections in a zebrafish embryo model of disseminated candidiasis.
Insights
New iridium complexes show potent antifungal activity against Candida species. The triflate-containing complex Ir1 effectively treats invasive fungal infections with low toxicity, offering a promising alternative to existing antifungals.
Area of Science:
- Inorganic Chemistry
- Medicinal Chemistry
- Mycology
Background:
- Candida species are opportunistic yeasts causing significant hospital-acquired fungal infections.
- High morbidity, mortality, and rising antifungal resistance necessitate novel therapeutic agents.
- Limited effective treatments highlight the urgent need for new antifungal mechanisms.
Purpose of the Study:
- To synthesize and evaluate novel half-sandwich iridium(III) complexes for antifungal activity.
- To investigate the structure-activity relationship concerning the counterion in iridium complexes.
- To assess the efficacy and mechanism of action of the most potent complex against Candida species.
Main Methods:
- Synthesis of two iridium(III) complexes, [Ir(η⁵-Cp*)Cl(N, N)]X, differing in counterion (triflate vs. chloride).
- In vitro antifungal susceptibility testing (MIC) against medically relevant fungi, including fluconazole-resistant strains.
- Assessment of biofilm inhibition, reactive oxygen species (ROS) induction, and in vivo efficacy in a zebrafish embryo model.
Main Results:
- Both complexes showed antifungal activity, with the triflate complex (Ir1) exhibiting superior potency (MICs 0.3–0.5 µM) against Candida spp.
- Ir1 outperformed caspofungin and fluconazole in vitro and retained activity against resistant strains.
- Ir1 inhibited biofilm formation, induced ROS, and demonstrated low toxicity and effective treatment of invasive candidiasis in vivo.
Conclusions:
- The triflate-containing iridium(III) complex Ir1 is a highly effective antifungal agent against Candida species.
- Ir1 demonstrates a novel mechanism of action, potentially involving ROS induction.
- Ir1 shows promise as a novel therapeutic for invasive fungal infections due to its efficacy and low toxicity.
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