Sources of Antifungal Drugs.

Due to their eukaryotic heritage, the differences between a fungal pathogen's molecular makeup and its human host are small. Therefore, the discovery and subsequent development of novel antifungal drugs are extremely challenging. Nevertheless, since the 1940s, researchers have successfully uncovered potent candidates from natural or synthetic sources. Analogs and novel formulations of these drugs enhanced the pharmacological parameters and improved overall drug efficiency. These compounds ultimately became the founding members of novel drug classes and were successfully applied in clinical settings, offering valuable and efficient treatment of mycosis for decades. Currently, only five different antifungal drug classes exist, all characterized by a unique mode of action; these are polyenes, pyrimidine analogs, azoles, allylamines, and echinocandins. The latter, being the latest addition to the antifungal armamentarium, was introduced over two decades ago. As a result of this limited arsenal, antifungal resistance development has exponentially increased and, with it, a growing healthcare crisis. In this review, we discuss the original sources of antifungal compounds, either natural or synthetic. Additionally, we summarize the existing drug classes, potential novel candidates in the clinical pipeline, and emerging non-traditional treatment options.

Fungal persister cells: The basis for recalcitrant infections?

Persister cells are a small subpopulation within fungal biofilms that are highly resistant to high concentrations of antifungals and therefore most likely contribute to the resistance and recalcitrance of biofilm infections. Moreover, this subpopulation is defined as a nongrowing, phenotypic variant of wild-type cells that can survive high doses of antifungals. There are high degrees of heterogeneity and plasticity associated with biofilm formation, resulting in a strong variation in the amount of persister cells. The fraction of these cells in fungal biofilms also appear to be dependent on the type of substrate. The cells can be observed immediately after their adhesion to that substrate, which makes up the initial step of biofilm formation. Thus far, persister cells have primarily been studied in Candida spp. These fungi are the fourth most common cause of nosocomial systemic infections in the United States, with C. albicans being the most prevalent species. Remarkably, persisters exhibit characteristics of a dormant state similar to what is observed in cells deprived of glucose. This dormant state, together with attachment to a substrate, appears to provide the cells with characteristics that help them overcome the challenges with fungicidal drugs such as amphotericin B (AmB). AmB is known to induce apoptosis, and persister cells are able to cope with the increase in reactive oxygen species (ROS) by activating stress response pathways and the accumulation of high amounts of glycogen and trehalose-two known stress-protecting molecules. In this review, we discuss the molecular pathways that are involved in persister cell formation in fungal species and highlight that the eradication of persister cells could lead to a strong reduction of treatment failure in a clinical setting.

Antifungal Activity of Oleylphosphocholine on In Vitro and In Vivo Candida albicans Biofilms.

In this study, we investigated the potential antifungal activity of the alkylphospholipid oleylphosphocholine (OlPC), a structural analogue of miltefosine, on in vitro and in vivoCandida albicans biofilm formation. The effect of OlPC on in vitro and in vivoC. albicans biofilms inside triple-lumen polyurethane catheters was studied. In vivo biofilms were developed subcutaneously after catheter implantation on the lower back of Sprague-Dawley rats. Animals were treated orally with OlPC (20 mg/kg of body weight/day) for 7 days. The effect of OlPC on biofilms that developed on the mucosal surface was studied in an ex vivo model of oral candidiasis. The role of OlPC in C. albicans morphogenesis was investigated by using hypha-inducing media, namely, Lee, Spider, and RPMI 1640 media. OlPC displayed activity against both planktonic cells and in vitroC. albicans biofilms. To completely abolish preformed, 24-h-old biofilms, higher concentrations (8, 10, and 13 mg/liter) were needed. Moreover, OlPC was able to reduce C. albicans biofilms formed by caspofungin-resistant clinical isolates and acted synergistically when combined with caspofungin. The daily oral administration of OlPC significantly reduced in vivoC. albicans biofilms that developed subcutaneously. In addition, OlPC decreased biofilm formation on mucosal surfaces. Interestingly, the application of subinhibitory concentrations of OlPC already inhibited the yeast-to-hypha transition, a crucial virulence factor of C. albicans We document, for the first time, the effects of OlPC on C. albicans cells and suggest the potential use of OlPC for the treatment of C. albicans biofilm-associated infections.