Fungal Pathogens: Life Cycle, Infection, Host Immunity, and Drug Discovery

Combating fungal infections has been a low-priority area in infectious disease management. Only recently did the medical community realize that the control of fungal infections and diseases must be brought to the central stage of global healthcare management. An estimated 6.5 million humans suffer from fungal infections annually, leading to over 3.8 million deaths. (1) The last two decades have witnessed the emergence of new fungal pathogens and a surge in antifungal drug resistance. Accurate diagnostic techniques and clinically approved antifungals remain limited, primarily due to poor understanding of the pathobiology of the organisms, posing hurdles in combating rapidly evolving fungal species. In 2022, the World Health Organization (WHO) put forth a priority list, categorizing the major fungal pathogens as critical, high, and medium priority, thus emphasizing the need to understand the biology of such organisms better. (2) This is undoubtedly a milestone, representing our rising awareness of fungal diseases and infections. The understanding of fungal pathogens’ biology is still in its infancy. Arguably, the best characterized fungal pathogen Candida albicans, has only 66% of its genes uncharacterized and is considered a model organism. (3) Over 90% of total number of estimated genes remain uncharacterized in other critical and high priority pathogens such as Nakaseomyces glabrata, Candida parapsilosis, and Candidozyma. Identifying and targeting fungal-specific cellular structures with potent drug molecules necessitates a comprehensive knowledge of the cellular pathways and proteins exclusively present in fungi but absent in humans. It is also essential to understand how fungal pathogens develop drug resistance and evade the host immune system. The period from 1950 to early 2000s witnessed the discovery of most antifungal compounds used to date for treating fungal infections. These include polyene, first generation triazoles, the pyrimidine analogue flucytosine, and echinocandins. Unfortunately, the drugs currently in clinical use have their own drawbacks. Amphotericin B is associated with infusion-related toxicity and nephrotoxicity, while monotherapy using flucytosine is not recommended due to serious side effects. Echinocandins are ineffective against major pathogens like Cryptococcus neoformans, thus restricting their activity spectrum. Rising resistance against triazoles underlines the need to search for new compounds with antifungal activity. (4) Extensive medicinal chemistry and structure–activity relationship studies performed in the past two decades yielded second-generation antifungals consisting of new additions to the azole drug class. While a lot of emerging therapeutics are in late phases of clinical development, challenges with respect to the pharmacokinetic understanding, spectrum of activity, and associated toxicity slow down the clinical translation of new classes of antifungals. Besides these reasons, the hunt for new antifungals is also gaining momentum as new pan-resistant species like C. auris have made their entry and proved that they are here to stay. While some fungi are beneficial to humans and most of them are harmless, when it comes to understanding only a few unfriendly members of the fungal kingdom, the woods are indeed dark and deep, and we have miles to go ahead of us. The central challenge we face today is finding potent fungal-specific targets or molecules, as fungi and humans share a significant number of common pathway genes, both being eukaryotes. The search for novel antifungal agents in the form of new targets, new structures for existing drug targets, and new members structurally similar to the existing antifungal classes is ongoing. Furthermore, phenotypic resistance to antifungals, mediated through biofilm formation, persistence, metabolic alteration, etc. also complicates therapy, and negatively affects treatment outcomes. (5) Another critical factor when considering systemic fungal infections is the prevalence of bacteria–fungi coinfection and polymicrobial biofilms. Such polymicrobial infections are inherently more robust, evade antimicrobial therapy, and often lead to recalcitrance. (6) Any new therapeutic modality has to factor some of these challenges also, if it is to emerge as a successful alternative to the existing options. Through this Special Issue, we have attempted to provide a platform to some of the most recent and crucial research on fungal pathogens, covering aspects such as pathogen life cycle, successful pathogenesis mechanisms, host interactions, and proposed therapeutic antifungal strategies. It features perspectives and reviews, providing insights into the biology of pathogens such as Candida glabrata, and the pathobiology of fungal infections such as keratitis, endophthalmitis, as well as insights into conjugated antifungal therapeutics. In addition, a diverse set of articles and letters explore the potential of drug cocktails, synergistic therapy, host–fungus interactions, antifungal vaccines, pathology of hyphae formation, etc. A significant number of articles discuss emerging antifungal drug discovery, covering antifungal small molecules, natural products, polymeric and nanotherapeutics, novel azoles, and host-mediated therapeutics, targeting key fungal pathogens such as Aspergillus, Candida, Cryptococcus, etc. We hope this Special Issue serves as a rich and updated resource of information and inspiration for the readers, facilitating more collaborative research between medicinal chemists, biomaterials researchers, clinicians, microbiologists, and chemical biologists─a need of the hour to equip ourselves in combating hostile members of the fungal kingdom. This article references 6 other publications. This article has not yet been cited by other publications.