Candida albicans is an opportunistic fungus [1] and the causative organism of invasive diseases in humans [2]. Every year, hundreds of millions of affected people experience symptoms due to C. albicans infections [3]. Surface infections and invasive systemic infections with significant mortality are the characteristic presentations of this disease [[4], [5], [6]]. Patients who are immunocompromised such as those with cancer and/or receiving chemotherapy, individuals with acquired immunodeficiency syndrome, and immunosuppressed patients with medical implants are susceptible to highly severe C. albicans infections [7,8].

Systemic or local antifungal medications such as fluconazole (FLC) and nystatin have been successfully used in recent years to treat and prevent C. albicans colonization and other invasive fungal infections. However, the overuse and long-term use of antibiotics have led to a significant attenuation in the susceptibility of C. albicans to antifungal agents owing to an increase in the number of drug-resistant strains and alteration in the virulence of the causative organism. Resistance to C. albicans is therefore a challenge that warrants the identification of novel therapeutic agents urgently [9].

Metal-containing drugs have been routinely used for the identification and management of illnesses. The US Food and Drug Administration's approval of cisplatin for clinical use has substantially accelerated the development of transition metal-containing drugs [10,11]. These drugs have numerous benefits over conventional organic compounds, including stability, desirable photophysical characteristics, distinctive electrochemical properties, and the ease of structural modifications [[12], [13], [14]]. Transition metal complexes exert anticancer, antidiabetic, antiparasitic, and antibacterial effects [15,16]. The antibacterial properties of several metal complexes, including copper (II) [17], silver (I) [18], rhodium (III) [19], and ruthenium (II) [20], have been recently discovered. Among them, ruthenium (II) and (III) complexes have traditionally received considerable attention as antibacterial agents owing to their selective antimetastatic effect and low systemic toxicity [16,21]. Liao and Wang [22] reported the potent bactericidal action of polypyridine ruthenium complexes modified with glycyrrhetinic acid against Staphylococcus aureus. Lam et al. [23] demonstrated that ruthenium (II) bis (2,2′-bipyridyl) complexes containing N-phenyl-substituted diazafluorenes exhibited excellent efficacy against methicillin-resistant S. aureus. However, there are relatively few reports on the antifungal activity of ruthenium complexes [24].

In this study, we synthesized a series of polypyridyl ruthenium (II) complexes having the formula [Ru (NN)2 (bpm)] (PF6)2 (N-N = 2,2′-bipyridine (bpy, in Ru1), 1,10-phenanthroline (phen, in Ru2), 4,7-diphenyl-1,10-phenanthroline (DIP, in Ru3) (bpm = 2,2′-bipyrimidine) and studied their antifungal activities. The minimum inhibitory concentration (MIC) and fractional inhibitory concentration index (FICI) of Ru1–Ru3 against C. albicans were investigated. Moreover, the time required for the optimal antifungal effect of the lead compound Ru3 in combination with FLC on drug-resistant C. albicans, its ability to prevent biofilm formation, its effect on the changes in mycelial morphology, its impact on the accumulation of reactive oxygen species (ROS), and its influence on fungal cell membrane permeability and structural integrity were evaluated. A mouse model of invasive C. albicans infection was used simultaneously for the preliminary evaluation of the drug combination. In this study, the antifungal experiment in vitro was combined with the anti-invasive infection experiment in vivo to comprehensively investigate the therapeutic effect of concomitant Ru3 and FLC. Although the structure of the three compounds has been reported earlier, their antifungal effect has not been studied. A thorough screening revealed the antifungal activity of the three structures. Their activities were also verified to contribute to the development of new strategies for antifungal treatment. We anticipate that the findings of our study will help develop novel treatment approaches to enhance the therapeutic efficacy of the synthesized antifungals in treating drug-resistant infections.