Iuri C. Barcellos

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.

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.

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.

Over the last years, the interkingdom microbial interactions concerning bacteria and fungi cohabiting and/or responsible for human pathologies have been investigated. In this context, the Gram-negative bacterium Pseudomonas aeruginosa and fungal species belonging to the Scedosporium/Lomentospora genera are widespread, multidrug-resistant, emergent, opportunistic pathogens that are usually co-isolated in patients with cystic fibrosis. The available literature reports that P. aeruginosa can inhibit the in vitro growth of Scedosporium/Lomentospora species; however, the complex mechanisms behind this phenomenon are mostly unknown. In the present work, we have explored the inhibitory effect of bioactive molecules secreted by P. aeruginosa (3 mucoid and 3 non-mucoid strains) on S. apiospermum (n = 6 strains), S. minutisporum (n = 3), S. aurantiacum (n = 6) and L. prolificans (n = 6) under cultivation in a cystic fibrosis mimic environment. It is relevant to highlight that all bacterial and fungal strains used in the present study were recovered from cystic fibrosis patients. The growth of Scedosporium/Lomentospora species was negatively affected by the direct interaction with either mucoid or non-mucoid strains of P. aeruginosa. Moreover, the fungal growth was inhibited by the conditioned supernatants obtained from bacteria-fungi co-cultivations and by the conditioned supernatants from the bacterial pure cultures. The interaction with fungal cells induced the production of pyoverdine and pyochelin, 2 well-known siderophores, in 4/6 clinical strains of P. aeruginosa. The inhibitory effects of these four bacterial strains and their secreted molecules on fungal cells were partially reduced with the addition of 5-flucytosine, a classical repressor of pyoverdine and pyochelin production. In sum, our results demonstrated that distinct clinical strains of P. aeruginosa can behave differently towards Scedosporium/Lomentospora species, even when isolated from the same cystic fibrosis patient. Additionally, the production of siderophores by P. aeruginosa was induced when co-cultivated with Scedosporium/Lomentospora species, indicating competition for iron and deprivation of this essential nutrient, leading to fungal growth inhibition.

The multidrug-resistant species belonging to the Scedosporium genus are well recognized as saprophytic filamentous fungi found mainly in human impacted areas and that emerged as human pathogens in both immunocompetent and immunocompromised individuals. It is well recognized that some fungi are ubiquitous organisms that produce an enormous amount of extracellular molecules, including enzymes and secondary metabolites, as part of their basic physiology in order to satisfy their several biological processes. In this context, the molecules secreted by Scedosporium species are key weapons for successful colonization, nutrition and maintenance in both host and environmental sites. These biologically active released molecules have central relevance on fungal survival when colonizing ecological places contaminated with hydrocarbons, as well as during human infection, particularly contributing to the invasion/evasion of host cells and tissues, besides escaping from the cellular and humoral host immune responses. Based on these relevant premises, the present review compiled the published data reporting the main secreted molecules by Scedosporium species, which operate important physiopathological events associated with pathogenesis, diagnosis, antimicrobial activity and bioremediation of polluted environments.