The World Health Organization included Cryptococcus neoformans and Cryptococcus gattii in its priority fungal pathogen list due to their high mortality rates and frequent treatment failures. These facts have driven research toward the discovery of new compounds for the treatment of cryptococcosis. In this study, we investigated the therapeutic potential of two complexes, [Cu(phendione)₃](ClO₄)₂·4H₂O (Cu-phendione) and [Ag(phendione)₂]ClO₄ (Ag-phendione), against drug-resistant clinical isolates of C. gattii and C. neoformans. Both complexes demonstrated anti-Cryptococcus activity, with Cu-phendione exhibiting minimum inhibitory concentration (MIC) values of 6.25 μM for C. gattii and 3.125 μM for C. neoformans, while Ag-phendione showed an MIC of 1.56 μM for both Cryptococcus species. Notably, both Cu-phendione and Ag-phendione complexes exhibited enhanced antifungal activity against reference strains of C. neoformans and C. gattii. In silico analysis identified both complexes as highly promising, exhibiting good oral bioavailability, high gastrointestinal absorption, and moderate skin permeability. Moreover, neither complex demonstrated toxicity toward sheep erythrocytes at concentrations up to 62.5 μM, with a selectivity index (SI) exceeding 10 for Cu-phendione and 40 for Ag-phendione. In vivo testing using the Galleria mellonella model demonstrated that both complexes were non-toxic, with 100% larval survival at concentrations up to 1000 μM and SI exceeding 160 following a single administration. Interestingly, larvae exposed to Cu-phendione at concentrations of 15.6–31.25 μM exhibited a significant increase in the density of hemocytes, the immune cells responsible for defense in invertebrates. Furthermore, multiple treatments with 62.5 μM of complexes caused either no larval mortality, hemocyte alterations, or changes in silk production or coloration, indicating a lack of toxicity. These findings suggest that Cu-phendione and Ag-phendione may serve as promising antifungal alternatives against Cryptococcus, with minimal host toxicity.

Background/Objectives: Fonsecaea pedrosoi causes chromoblastomycosis, a neglected chronic subcutaneous mycosis that remains difficult to treat. In this study, we evaluated the toxicity and the antifungal effect of [Ag(1,10-phenanthroline)₂]ClO₄ (Ag-phen) and [Ag₂(3,6,9-trioxaundecanedioate)(1,10-phenanthroline)₄]·EtOH (Ag-tdda-phen) against F. pedrosoi using in silico, in vitro and in vivo approaches. Methods: Pharmacokinetic and toxicological parameters were predicted using ADMETlab 2.0. The toxicity of the complexes was assessed using sheep red blood cells, RAW 264.7 macrophage cells, and larvae of Tenebrio molitor and Galleria mellonella. The effects of these complexes on macrophage adhesion capacity and reactive oxygen species (ROS) production were also investigated using Giemsa staining and dichlorofluorescein diacetate, respectively. In addition, their impact on the survival of G. mellonella larvae infected with conidia was evaluated. Results: Overall, computational analyses predicted favorable tolerability profiles for both complexes. In vitro assays with red blood cells and macrophages demonstrated that they exhibited selectivity indexes >10 against F. pedrosoi. These findings were corroborated by in vivo experiments in which both complexes were injected into insect larvae; the complexes demonstrating good tolerability at concentrations of up to 500 mg/L. Macrophage infection assays revealed that Ag-tdda-phen and Ag-phen markedly reduced the number of intracellular conidia. These effects appear to be associated with oxidative stress, as macrophage production of ROS significantly increased following treatment with the complexes. Furthermore, Ag-tdda-phen improved the survival of G. mellonella larvae infected with F. pedrosoi, demonstrating a protective effect. Conclusions: Collectively, our findings support the notion that silver(I)-phen derivatives represent promising candidates for the development of therapeutic options against CBM infections caused by F. pedrosoi.

Pseudomonas aeruginosa and Scedosporium/Lomentospora often coexist in the lungs of cystic fibrosis patients, where their interaction can affect disease outcomes. Our group has recently demonstrated that P. aeruginosa suppresses the growth of Scedosporium/Lomentospora species partly through mechanisms involving iron sequestration. In this study, we have investigated how molecules secreted by P. aeruginosa under high (36 µM) and low (3.6 µM) iron conditions affect the planktonic growth and biofilm formation by S. apiospermum, S. minutisporum, S. aurantiacum and L. prolificans. Although P. aeruginosa exhibited enhanced proliferation under high-iron conditions, spectrophotometric analyses revealed a marked increase in phenazine and pyoverdine production under low-iron conditions, with siderophore activity confirmed by Chrome Azurol S assays. Supporting these findings, supernatants from P. aeruginosa cells grown under iron limitation markedly inhibited fungal growth (≈30%) and biofilm formation (≈70%), whereas those from high-iron cultures were less effective. Notably, low-iron bacterial-free supernatants exhibited pronounced cytotoxic effects on mammalian cells, reducing metabolic activity by an average of 20% in A549 lung epithelial cells and 40% in THP-1 macrophages, and significantly compromising survival in the Tenebrio molitor infection model, resulting in 100% larval mortality within 7 days. Collectively, these results indicate that the antifungal activity of P. aeruginosa is closely coupled with increased host toxicity. Moreover, the results demonstrate that environmental iron availability plays a critical role in modulating both antifungal activity and toxicity, thereby shaping P. aeruginosa interactions with Scedosporium/Lomentospora species. Such iron-dependent dynamics may influence the progression and severity of respiratory co-infections, with important implications for patient management and therapeutic interventions.

1,10-Phenanthroline-5,6-dione (phendione) is a functionalized derivative of 1,10-phenanthroline bearing two carbonyl groups at the 5,6-positions, which enhance its electron-accepting ability, polarity and coordination versatility. These structural features enable phendione to act as a bidentate ligand for a variety of transition metals, forming stable coordination compounds (or complexes) widely explored in coordination chemistry, catalysis, materials science and redox systems. In addition, phendione and its metal complexes have demonstrated relevant biological activities, including antibacterial, antifungal and antiprotozoal effects, attributed to DNA interaction, redox cycling, inhibition of key enzymes and interference with essential microbial processes such as protein synthesis. In the context of the escalating global burden of antimicrobial resistance, the discovery and development of innovative therapeutic strategies have become an urgent priority. In this scenario, phendione-based complexes have emerged as promising candidates owing to their remarkable structural diversity, versatile coordination chemistry, tunable physicochemical properties and ability to engage multiple and distinct mechanisms of action that differ from those of currently available clinical antimicrobial drugs. These characteristics provide opportunities for overcoming existing therapeutic limitations and expanding the arsenal of antimicrobial agents, particularly against clinically relevant pathogenic microorganisms, including multidrug- and pan-resistant strains for which effective treatment options remain critically limited. The present review provides a comprehensive and critical analysis of the current literature concerning the synthesis, structural features and antimicrobial properties of phendione-containing complexes, highlighting their potential as promising next-generation antimicrobial agents and exploring their mechanisms of action, biological relevance and future perspectives in the development of innovative therapies.