Critical steps in fungal cell wall synthesis: Strategies for their inhibition (original) (raw)

Antifungal Agents That Target Fungal Cell Wall Components : A Review

2015

The fungal cell wall represents an exclusive structure that confers mechanical strength and osmotic resistance to fungal cells. The fungal cell wall’s structure contains mainly mannan, chitins and glucans in different proportions depending on the species. These structural components are unique to fungi and are currently being investigated as targets for novel antifungals. Currently, glucan component of the cell wall is the predominant target for therapeutic applications and developments of antifungals. Three classes of glucan inhibitors in application includes the lipopeptides e.g. echinocandins, the glycolipid papulacandins and the acid terpenoids including enfumafungin and ascosterosides. These agents are known 1,3-β-d glucan synthesis inhibitors and have been shown to possess antifungal activity in vitro as well as in vivo in many different animal models against yeasts e.g. Candida and filamentous fungi e.g. Aspergillus. The other targets, chitin and mannan are however being inve...

Antifungal agents: mechanisms of action

Trends in Microbiology, 2003

Clinical needs for novel antifungal agents have altered steadily with the rise and fall of AIDS-related mycoses, and the change in spectrum of fatal disseminated fungal infections that has accompanied changes in therapeutic immunosuppressive therapies. The search for new molecular targets for antifungals has generated considerable research using modern genomic approaches, so far without generating new agents for clinical use. Meanwhile, six new antifungal agents have just reached, or are approaching, the clinic. Three are new triazoles, with extremely broad antifungal spectra, and three are echinocandins, which inhibit synthesis of fungal cell wall polysaccharides – a new mode of action. In addition, the sordarins represent a novel class of agents that inhibit fungal protein synthesis. This review describes the targets and mechanisms of action of all classes of antifungal agents in clinical use or with clinical potential.

An Overview on Antifungal Drug Therapy

Asian journal of pharmaceutical research and development, 2023

Nowadays, the majority of fungal infections, including candidiasis, can cause anything from a minor mucous membrane infection to fatal systemic mycoses. Due to the most rapid increase in populations with impaired hosts, such as those with HIV/AIDS, organ transplant recipients, and chemotherapy patients, candida infections present a serious clinical challenge internationally. In addition, a dramatic rise in the number of elderly people who are vulnerable to fungal infections is anticipated in the next decades. Due to the eukaryotic structure of the cells, developing antifungal medications for these issues is more challenging than developing antibacterial medications. Therefore, there are now only a limited number of antifungal medications available to treat the wide range of fungal infections. Additionally, the antifungal arsenal against fungal diseases has been constrained by the rise in antifungal resistance and unfavourable host effects.

The biology and chemistry of antifungal agents: A review

Bioorganic & Medicinal Chemistry, 2012

In recent years their has been an increased use of antifungal agents and has resulted in the development of resistance to drugs. Currently, use of standard antifungal therapies can be limited because of toxicity, low efficacy rates. Different types of mechanisms contribute to the development of resistance to antifungals. This has given raise to search for a new heterocycle with distinct action or multitargeted combination therapy. This review addresses the areas such as the underlying mechanisms, eight different targets such as ergosterol synthesis, chitin synthesis, ergosterol disruptors, glucan synthesis, squalene epoxidase, nucleic acid synthesis, protein synthesis, microtubules synthesis. The clinically employed drugs along with the current research work going on worldwide on different heterocycles are discussed. In recent advances various heterocycles including imidazole, benzimidazole etc., twenty three scaffolds and their lead identification are discussed.

New Cell Wall-Affecting Antifungal Antibiotics

Antimicrobial Compounds: Current Strategies and New Alternatives, 2013

Fungi have emerged worldwide as increasingly frequent causes of healthcare-associated infections. Invasive fungal infections can be life-threatening. However, the number of antifungal agents available and their use in therapy is very limited. Recently, a new family of specific fungal cell wall synthesis inhibitors has emerged as an alternative antifungal therapy and is gaining increasing relevance yearly. The cell wall is a multilayer dynamic structure, essential to the integrity and shape of the fungal cell, whose function is to counteract the osmotic forces that could otherwise produce fungal cell lysis. The cell wall is absent in nonfungal cells, therefore representing a useful target in discovering selective drugs for the treatment of fungal infections without causing toxicity in the host. Although fungi exhibit a considerable diversity in their cell wall structure, all present b(1,3)-, b(1,6)- and a(1,3)-glucans, chitin, and mannoproteins as their major cell wall components. Three different cell wall synthesis inhibitors of the lipopeptide family of echinocandins, named caspofungin, micafungin, and anidulafungin, are commercially available and new classes of cell wall synthesis inhibitors are emerging. This review provides an overview of what is so far known about the different classes of cell wall-affecting antifungal agents and their mechanism of action, offering new alternatives with clinical potential.

Recent Trends in Antifungal Agents and Antifungal Therapy

Springer eBooks, 2016

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An Overview on Antifungal Therapy

International Journal of Biomedical and Advance Research, 2011

The number of fungi causing systemic disease is growing and the number of systemic diseases caused by fungi is increasing. The currently available antifungal agents for the treatment of systemic mycoses include polyene antibiotics (Amphotericin B), fluoropyrimidine (Flu cytosine), and Nystatin andazole group of drugs (Ketoconazole, Fluconazole, and Itraconazole). Novel drug delivery systems for antifungal therapy, based on the type of formulation are classified as Liposomes Nanocochleates, Nanospheres, Carbon Nanotubes, Doubled layered Mucoadhesive Tablets, Mucoadhesive Thermo Sensitive Pronged release gels, and Parenteral Micro emulsions. Amphotericin B is the only fungicidal agent available and is the 'goldstandard' for the treatment of most of the systemic mycoses. The three currently available lipid formulations are Amphotericin B Lipid Complex (ABLC), Amphotericin B Colloidal Dispersion (ABCD) and Liposomal Amphotericin B (L-AmB). Nystatin and ketoconazole are also commercially available as liposomes. Novel Drug delivery systems for antifungal therapy, aiming at reducing the side effects and maximizing the antifungal activity have added a new dimension to the treatment of fungal infections. Without fungi we would not have bread, beer, wine or antibiotics, but more importantly without the nutrient recycling and plant nutrition provided by fungi-we probably could not survive at all.

Recent Advances in Antifungal Agents

Mini-Reviews in Medicinal Chemistry, 2007

New antifungals are needed in the medicine because of more aggressive and invasive diagnostic and therapeutic methods used, rapid emergence of resistant and new opportunistic fungi, increasing number of patients suffering from immunosuppressive situations e.g., AIDS, transplantation, cancer, etc. Several classes of new antifungal agents are discussed here including some new members of known families. Voriconazole, posaconazole and ravuconazole, are novel triazoles that inhibit the ergosterol synthesis. These drugs overcome problems associated with the ineffectivity of fluconazole against some Aspergillus spp. or the variable bioavailability of itraconazole. Echinocandins (caspofungin, anidulafungin and micafungin) represent a new family of antifungal agents that inhibit 1,3-glucan synthase. Nikkomycins targeting the chitin synthase, show activity against Histoplasma capsulatum and Blastomyces dermatitidis. Sordarin derivatives that block the fungal protein synthesis can be considered as a promising new class of antifungal agents for the treatment of Candida and Pneumocystis infections.

Antifungal agents: An overview. Part II

Journal of the American Academy of Dermatology, 1994

The recent introductionof a newgenerationof antifungal drugs promisesto alter significantly therapy for both systemicand superficial mycoses, in particular, onychomycosis. This article presents an in-depth review of the azoles(the triazoles itraconazole and fluconazole), the allylamines (naftifineand terbinafine), and the morpholinederivative amorolfine. (J AMACAD DERMATOL 1994;30:911-33.) Learning objective: At the conclusion of this learning activity, participants should be able to discussselected new approachesto antifungal drug therapy for superficial and systemic mycoses, especially onychomycosis.

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.