New Antifungal Drugs: Discovery and Therapeutic Potential

There has been an increase in invasive fungal infections, which are a universal problem due to the longer average lifespan, the number of immunocompromised patients associated with high morbidity/mortality rates, and the appearance of resistance to antifungals. In addition, certain fungal infections that emerged during the COVID-19 pandemic reinforced the action of searching for new antifungal alternatives. One example is the fungus Aspergillus fumigatus for which mortality reached 80% among severe COVID-19 patients infected with it. Despite the urgent need for more antifungal drug options, no new classes of antifungal drugs have become available over the last two decades. Current antifungal therapies have many limitations: poor oral bioavailability, narrow therapeutic indexes, and emerging drug resistance, and it is essential to discover and develop novel drugs, which can overcome these limitations and be added to the antifungal armamentarium. This review is an extension of another one published in 2016, and it covers the discovery and potential of the most promising antifungal agents developed since then: fosmanogepix (1) (a novel Gwt1 enzyme inhibitor), ibrexafungerp (an enfumafungin derivative, the first representative of a novel class of structurally distinct glucan synthase inhibitors, and triterpenoids), rezafungin (an echinocandin designed to be given as a weekly dose), encochleated amphotericin B (CAMB), oteseconazole (VT-1161), VT-1598, VT-1129 and opelconazole PC945, (novel tetrazole-specific Cyp51 inhibitors), and olorofim (a novel dihydroorotate dehydrogenase enzyme inhibitor). These new drugs, as well as new agents developed as new formulations of existing antifungal classes, offer advantages over current therapies and new mechanisms of action for overcoming resistance, improving safety profiles, reducing interactions, and improving the potential role of these drugs in relation to unmet needs in the future.