Targeting virulence: A new paradigm for antifungals (original) (raw)
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Aspartic Protease Inhibitors: Effective Drugs against the Human Fungal Pathogen Candida albicans
Mini-Reviews in Medicinal Chemistry
Candida albicans can invade humans and may lead to mucosal and skin infections or to deep-seated mycoses of almost all inner organs, especially in immunocompromised patients. In this context, both the host immune status and the ability of C. albicans to modulate the expression of its virulence factors are relevant aspects that drive the candidal susceptibility or resistance; in this last case, culminating in the establishment of successful infection known as candidiasis. C. albicans possesses a potent armamentarium consisting of several virulence molecules that help the fungal cells to escape from the host immune responses. There is no doubt that the secretion of aspartic proteases, designated as Saps, is one of the major virulence attributes produced by C. albicans cells, since these hydrolytic enzymes participate in a wide range of fungal physiological processes as well as in different facets of the fungal-host interactions. For these reasons, Saps clearly hold promise as new potential drug targets. Corroborating this hypothesis, the introduction of anti-human immunodeficiency virus drugs of the aspartic protease inhibitor-type (HIV PIs) have emerged as new agents for the inhibition of Saps. The introduction of HIV PIs has revolutionized the treatment of HIV disease, reducing the opportunistic infections, especially candidiasis. The attenuation of candidal infections in HIV-infected individuals might not solely has not only resulted from improved immunological status, but also as a result of direct inhibition of C. albicans Saps as well as the blockage of several biological processes controlled by these proteolytic enzymes. The present article will discuss the updates on the functional implications of HIV PIs on the development of candidiasis.
Antifungals: Need to search for a new molecular target
Indian Journal of Pharmaceutical Sciences, 2008
Sangamwar, et al.: Strategies for antifungal targets In the 1990s, drug resistance has become an important problem in a variety of infectious diseases including human immunodefi ciency virus infection, tuberculosis, and other bacterial infections which have profound effects on human health. At the same time, there have been dramatic increase in the incidence of fungal infections, which are probably the result of alterations in immune status associated with the acquired immuno defi ciency syndrome epidemic, cancer chemotherapy, and organ and bone marrow transplantation. The rise in the incidence of fungal infections has exacerbated the need for the next generation of antifungal agents, since many of the currently available drugs have undesirable side effects, are ineffective against new or reemerging fungi, or lead to the rapid development of the resistance. This review will focus on the pathogenic yeast Candida albicans, since a large body of work on the factors and mechanism associated with antifungal drug resistance in this organism is reported suffi ciently. It will certainly elaborate the probable molecular targets for drug design, discovered to date.
Alternative approaches to antifungal therapies
Experimental Dermatology, 2012
The expansive use of immunosuppressive medications in fields such as transplantational medicine and oncology, the higher frequency of invasive procedures in an ageing population and the HIV/AIDS pandemic have increased the frequency of systemic fungal infections. At the same time, increased resistance of pathogenic fungi to classical antifungal agents has led to sustained research efforts targeting alternative antifungal strategies. In this review, we focus on two promising approaches: cationic peptides and the targeting of fungal virulence factors. Cationic peptides are small, predominantly positively charged protein fragments that exert direct and indirect antifungal activities, one mechanism of action being the permeabilization of the fungal membrane. They include lysozyme, defensins and cathelicidins as well as novel synthetic peptides. Among fungal virulence factors, the targeting of candidal secreted aspartic proteinases seems to be a particularly promising approach.
Collection of Czechoslovak Chemical Communications, 1999
In an attempt to develop effective inhibitors of Candida secreted aspartic proteinases, we have prepared a series of N-protected peptides varying in the type of scissile bond replacement, in the P and P' side chains as well as in the N- and C-terminal modifications. The compounds were tested in vitro with the chromogenic peptide substrate using purified secreted proteinases of C. albicans and C. tropicalis. Our results have confirmed that the binding of inhibitors and their effectiveness is influenced by a number of enzyme-inhibitor interactions. Moreover, factors like solvation/desolvation contribute to the optimal binding energy of the inhibitors.
New trends in the search for alternative antifungal therapies
Pediatria i Medycyna Rodzinna, 2019
The paper addresses the issue of fungal infections in the context of growing resistance to currently available antifungal agents and the development of new antimycotics. Fungal pathogens belonging to the genuses Candida, Aspergillus, Pneumocystis and Cryptococcus account for about 90% of all fungal infections. Candida albicans infections are a global clinical problem, and systemic candidiasis is considered one of the most severe fungal infections, with mortality rates of about 40% despite treatment. Currently, there are five classes of antimycotics available, of which only three (azoles, echinocandins and polyenes) are used for systemic infections. The limited variety of available therapies as well as their overuse in both therapy and prevention have contributed to the growing resistance among fungal pathogens. Many mechanisms of resistance to antimycotics have been identified. These include in particular: mutations in genes encoding target proteins, increase or decrease in target protein, protein pump activity, biofilm formation or activation of stress response. The growing incidence of fungal infections and the difficulty of their treatment have forced the search for alternative therapeutic agents with new mechanisms of action. Due to the eukaryotic nature of fungal cells, recent trends in literature imply that novel agents should specifically target virulence factors or stress response of the pathogen.
Synergistic combinations of antifungals and anti-virulence agents to fight against Candida albicans
Virulence, 2015
Candida albicans, one of the pathogenic Candida species, causes high mortality rate in immunocompromised and high-risk surgical patients. In the last decade, only one new class of antifungal drug echinocandin was applied. The increased therapy failures, such as the one caused by multi-drug resistance, demand innovative strategies for new effective antifungal drugs. Synergistic combinations of antifungals and anti-virulence agents highlight the pragmatic strategy to reduce the development of drug resistant and potentially repurpose known antifungals, which bypass the costly and time-consuming pipeline of new drug development. Anti-virulence and synergistic combination provide new options for antifungal drug discovery by counteracting the difficulty or failure of traditional therapy for fungal infections.
Aspartic proteinases ofCandidaspp.: role in pathogenicity and antifungal resistance
Mycoses, 2013
Fungal infections represent a serious health risk as they are particularly prevalent in immunocompromised individuals. Candida spp. pathogenicity depends on several factors and secreted aspartic proteinases (Sap) are considered one of the most critical factors as they are associated with adhesion, invasion and tissue damage. The production of proteinases is encoded by a family of 10 genes known as SAP, which are distributed differently among the species. The expression of these genes may be influenced by environmental conditions, which generally result in a higher fungal invasive potential. Non-pathogenic Candida spp. usually have fewer SAP genes, which are not necessarily expressed in the genome. Exposure to subinhibitory concentrations of antifungal agents promotes the development of resistant strains with an increased expression of SAP genes. In general, Candida spp. isolates that are resistant to antifungals show a higher secretion of Sap than the susceptible isolates. The relationship between Sap secretion and the susceptibility profile of the isolates is of great interest, although the role of SAPs in the development of resistance to antifungal agents remains still unclear. This review is the first one to address these issues.
Recent advances on Candida albicans biology and virulence
F1000Research, 2016
Candida albicans is an important human fungal pathogen, in terms of both its clinical significance and its use as an experimental model for scientific investigation. Although this opportunistic pathogen is a natural component of the human flora, it can cause life-threatening infections in immunosuppressed patients. There are currently a limited number of antifungal molecules and drug targets, and increasing resistance to the front-line therapeutics, demonstrating a clear need for new antifungal drugs. Understanding the biology of this pathogen is an important prerequisite for identifying new drug targets for antifungal therapeutics. In this review, we highlight some recent developments that help us to understand how virulence traits are regulated at the molecular level, in addition to technical advances that improve the ability of genome editing in C. albicans.
Current Drug Targets, 2014
Despite of modern antifungal therapy, the mortality rates of invasive infection with human fungal pathogen Candida albicans are up to 40%. Studies suggest that drug resistance in the three most common species of human fungal pathogens viz., C. albicans, Aspergillus fumigatus (causing mortality rate up to 90%) and Cryptococcus neoformans (causing mortality rate up to 70%) is due to mutations in the target enzymes or high expression of drug transporter genes. Drug resistance in human fungal pathogens has led to an imperative need for the identification of new targets unique to fungal pathogens. In the present study, we have used a comparative genomics approach to find out potential target proteins unique to C. albicans, an opportunistic fungus responsible for severe infection in immune-compromised human. Interestingly, many target proteins of existing antifungal agents showed orthologs in human cells. To identify unique proteins, we have compared proteome of C. albicans [SC5314] i.e., 14,633 total proteins retrieved from the RefSeq database of NCBI, USA with proteome of human and non-pathogenic yeast Saccharomyces cerevisiae. Results showed that 4,568 proteins were identified unique to C. albicans as compared to those of human and later when these unique proteins were compared with S. cerevisiae proteome, finally 2,161 proteins were identified as unique proteins and after removing repeats total 1,618 unique proteins (42 functionally known, 1,566 hypothetical and 10 unknown) were selected as potential antifungal drug targets unique to C. albicans.