Promising Antifungal Targets Against Candida albicans Based on Ion Homeostasis

Abstract

In recent decades, invasive fungal infections have been increasing significantly, contributing to high incidences and mortality in immunosuppressed patients. Candida albicans (C. albicans) is the most prevalent opportunistic fungal pathogen in humans that can cause severe and often fatal bloodstream infections. Current antifungal agents have several limitations, including that only a small number of classes of antifungals are available, certain of which have severe toxicity and high cost. Moreover, the emergence of drug resistance is a new limitation to successful patient outcomes. Therefore, the development of antifungals with novel targets is an essential strategy for the efficient management of C. albicans infections. It is widely recognized that ion homeostasis is crucial for all living cells. Many studies have identified that ion-signaling and transduction networks are central to fungal survival by regulating gene expression, morphological transition, host invasion, stress response, and drug resistance. Dysregulation of ion homeostasis rapidly mediates cell death, forming the mechanistic basis of a growing number of compounds that elicit antifungal activity. Most of the potent antifungals have been widely used in the clinic, and certain of them have low toxicity, meaning that they may be expected to be used as antifungal drugs in the future. Hence, we briefly summarize the homeostasis regulation of several important ions, potential antifungal targets based on these ion-signaling networks, and antifungal compounds based on the disruption of ion homeostasis. This summary will help in designing effective drugs and identifying new targets for combating fungal diseases.

Synthesis, antimicrobial activity, and determination of the lipophilicity of ((cyclohex-3-enylmethylene)hydrazinyl)thiazole derivatives

“…Invasive candidiasis are considered the life-threatening infections associated with high morbidity and mortality (Pappas et al 2016;Hacioglu et al 2018). The mortality rate of bloodstream infections caused by these yeasts was reported to be as high as 40-60% among immunosuppressed and hospitalized patients (Sun et al 2015;Li et al 2018;Turecka et al 2018).…”

“…The incidence of fungal infection is increasing, especially in populations of immunosuppressed individuals (persons with HIV/AIDS or primary immune deficiency) and due to the continuous development of modern medicines, such as organ transplantation, hemodialysis, parenteral nutrition, extensive applicability of catheters or medical implants, cancer chemotherapy, and the widespread use of broad-spectrum antibiotics, glucocorticoids, and immunosuppressants (Turecka et al 2018;Roemer and Krysan 2014;Gomes da Silva Dantas et al 2018). In addition to the predisposing factors of the host, the pathogenicity of Candida species is affected by their virulence factors, such as the polymorphism (growth in two forms, unicellular and filamentous), production of extracellular enzymes (proteases, phospholipases, and hemolysins), as well as the expression of adhesins, which is related to the biofilm formation (on host tissues or on medical device surfaces) (Hacioglu et al 2018;Sun et al 2015;Li et al 2018;Gomes da Silva Dantas et al 2018).…”

“…At present, the available antifungal drugs are limited to three major classes: polyenes (amphotericin B or nystatin), which bind fungal cell membrane ergosterol leading to cell lysis; azoles (fluconazole or posaconazole) that inhibit ergosterol biosynthesis; and echinocandins (caspofungin or micafungin) inhibiting fungal (1,3)-β-D-glucan cell wall synthesis (Ishida et al 2011;Pappas et al 2016;Li et al 2018;Turecka et al 2018;Roemer and Krysan 2014;Ahmad et al 2017). Some characteristics of these drugs restrict their use in prophylaxis and clinical practice, such as fungistatic activity (azoles), which extends the required time of treatment, high toxicity (polyenes) and nonspecific interaction with other drugs, which increases their side effects (Gomes da Silva Dantas et al 2018;Ahmad et al 2017).…”

“…Moreover, as a consequence of the wide use of these antifungals, drug resistance of Candida spp. is increasing, which poses a serious threat to antifungal therapy (Li et al 2018). Thus, discovering new antifungal agents or overcoming drug resistance become a hot topic in the antifungal field (Li et al 2018;Ahmad et al 2017).…”

Multi-epitope Peptide Vaccine Prediction for Candida albicans targeting Pyruvate Kinase Protein; an Immunoinformatics Approach

“…1, [18][19][20][21][22][23] Adding to that, the prolonged use of antifungal agents such as azoles, polyenes, and echinocandinsin in immunocompromised individuals may lead to an increase in C. albicans resistance to many of the drugs used currently. 4,5,11,24 Over the last decades, several different anti-Candida vaccines have been suggested with Different strategies for immunization against candidiasis such as, live-attenuated fungi, recombinant proteins, and glycoconjugates2526,27.Among many vaccines candidates, two univalent subunit vaccines (Als3 and the Sap2 v) and one recombinant C. albicans adhesin/invasin protein (NDV-3A) have been under development in recent years but none has been approved by the FDA, yet. The difficulties originates from the ability of C. albicans to evolve rapidly and lose host immune system's recognition and the problem of how to trigger an immune responses in immunocompromised individuals.…”