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Fungal cell wall inhibitors: emphasis on clinical aspects
1Department of Haematology, University Hospital Gasthuisberg, Leuven, Belgium. johan.maertens@uz.kuleuven.ac.be
Abstract:
Invasive fungal infections, mainly caused by Candida and Aspergillus species, are an emerging cause of morbidity and mortality among all categories of immunocompromised patients. Currently available antifungal agents, both polyenes, flucytosine and (tri)azoles are hampered by serious infusion- or drug-related toxicity, by hazardous drug-drug interactions, or by pharmacokinetic problems and by the development of resistance, in vitro as well as in vivo. In recent years, several companies have become interested in antifungal drug development and have launched new compounds into preclinical and clinical trials. Some of these agents target the fungal cell wall in stead of the cell membrane. They exert their fungicidal action through inhibition of the synthesis of critical compounds of that fungal cell wall, not present in mammalian cells. Exciting and promising agents include inhibitors of beta-(1,3)-D-glucan synthase and inhibitors of chitin synthase. These drugs appear well tolerated in Phase I-II studies and will soon enter Phase III studies. This review wants to provide the clinical framework for assessing the utility of these agents compared to existing antifungals, thereby focusing on invasive fungal disease and emphasising the changing fungal epidemiology and susceptibility in immunocompromised hosts.
Insights
New antifungal drugs targeting the fungal cell wall show promise for immunocompromised patients. These agents, inhibiting beta-(1,3)-D-glucan synthase or chitin synthase, appear well-tolerated and may overcome limitations of current treatments for invasive fungal infections.
Area of Science:
- Mycology
- Infectious Diseases
- Pharmacology
Background:
- Invasive fungal infections (IFIs) pose significant risks to immunocompromised patients, with Candida and Aspergillus species being primary culprits.
- Existing antifungal therapies like polyenes, flucytosine, and azoles present challenges including toxicity, drug interactions, pharmacokinetic issues, and emerging resistance.
- The development of novel antifungal agents is crucial to address the limitations of current treatments and improve patient outcomes.
Purpose of the Study:
- To review the clinical framework for evaluating new antifungal agents targeting the fungal cell wall.
- To compare the efficacy and safety of novel antifungals with existing treatments for IFIs.
- To emphasize the evolving landscape of fungal epidemiology and susceptibility in immunocompromised hosts.
Main Methods:
- Review of preclinical and clinical trial data for novel antifungal compounds.
- Analysis of mechanisms of action for agents targeting fungal cell wall synthesis (e.g., beta-(1,3)-D-glucan synthase and chitin synthase inhibitors).
- Focus on clinical utility, safety profiles, and comparative effectiveness against established antifungals.
Main Results:
- New antifungal agents targeting fungal cell wall synthesis demonstrate promising tolerability in early-phase studies (Phase I-II).
- These novel compounds offer alternative mechanisms of action distinct from traditional cell membrane-targeting drugs.
- Agents inhibiting beta-(1,3)-D-glucan synthase and chitin synthase are advancing to Phase III clinical trials.
Conclusions:
- Novel antifungals targeting the fungal cell wall represent a significant advancement in managing IFIs.
- These agents have the potential to overcome resistance and toxicity issues associated with current therapies.
- Further clinical evaluation is essential to establish the role of these new drugs in the treatment of IFIs in immunocompromised populations.