Combatting the evolution of antifungal resistance in Cryptococcus neoformans

Abstract

Fungal infections are a global concern and the evolution of intrinsic resistance to current antifungals presents an alarming problem. For Cryptococcus neoformans, a human fungal pathogen of primarily immunocompromised individuals, resistance toward treatment strategies demands alternative approaches. Given the prevalence of virulence factor production during cryptococcal infection, an emerging and important field of research encompasses the development of novel antivirulence therapies proposed to improve host immune responses and promote fungal clearance. To accomplish this task, information regarding the presence and role of virulence factors, the mechanisms of action within the host, and the ability to influence fungal susceptibility to antifungals is pertinent. Research into mechanisms of antifungal resistance for C. neoformans is limited but extrapolation from successful studies in other fungal species can improve our understanding of mechanisms employed by C. neoformans and suggest targeted strategies to enhance our ability to combat the pathogen. In this Review, we highlight antifungal therapy options against Cryptococcus, explore current knowledge of underlying mechanisms promoting resistance, and present new opportunities for novel and effective strategies to overcome fungal infections and reduce, or possibly even reverse, the effects of resistance evolution.

Successful Treatment of Cryptococcal Meningitis and Cryptococcoma with Isavuconazole in a Patient Living with HIV

“…For this reason, the WHO recommends one week of Amphotericin B plus flucytosine, then one week of 1200 mg fluconazole for the 2 week induction of CM treatment [13]. Notably, of the 10 countries with the highest incidence of CM, at least 8 do not have access to flucytosine [14]. Despite international guideline recommendations, the vast majority of cases of CM are managed with high dose fluconazole for reasons outlined above; access to medication, mitigating of adverse events due to amphotericin B and flucytosine toxicity, and previous experience with fluconazole.…”

Post-Translational Modifications Drive Success and Failure of Fungal–Host Interactions

“…were not explored due to a lack of viable transformants or incorrect genotype, or persistence of the wild-type allele, suggesting that alternative strategies, such as interference CRISPR, may have application in C. neoformans [90,91]. Moreover, the application of anti-virulence therapeutics (i.e., antimicrobial agents that target virulence factors produced by the pathogen rather than the pathogen itself) supports clearance of the pathogen from the host while limiting the evolution of resistance [12,92].…”

“…Fungal infections are particularly prevalent among immunocompromised individuals, including those suffering from HIV/AIDS, cancer patients receiving immunotherapy, organ transplant recipients administered immunosuppressive drugs, as well as the elderly population [8]. Treatment of fungal infections is a serious challenge with a limited selection of low host toxicity, clinically effective antifungal drugs, and the emergence of resistant strains [9][10][11][12]. Among medically relevant fungal pathogens, Candida spp., Aspergillus spp., and Cryptococcus spp.…”

Experimental Evolution of Antifungal Resistance in Cryptococcus neoformans

“…The emergence of antifungal‐resistant Cryptococcus neoformans presents an alarming problem for global health, resulting in increased morbidity and mortality rates worldwide (Rajasingham et al., 2017). C. neoformans , a fungal pathogen that primarily affects immunocompromised individuals, has demonstrated resistance towards all the main classes of antifungal drugs used to combat cryptococcal meningitis (Bermas & Geddes‐McAlister, 2020). A simple, yet powerful tool to study antifungal resistance involves the experimental evolution of microbes as a means to identify and analyze the development of novel traits following prolonged exposure to an antifungal drug.…”