Aspiring Antifungals: Review of Current Antifungal Pipeline Developments

Abstract

Invasive fungal infections are associated with significant morbidity and mortality, and their management is restricted to a variety of agents from five established classes of antifungal medication. In practice, existing antifungal agents are often constrained by dose-limiting toxicities, drug interactions, and the routes of administration. An increasing prevalence of invasive fungal infections along with rising rates of resistance and the practical limitations of existing agents has created a demand for the development of new antifungals, particularly those with novel mechanisms of action. This article reviews antifungal agents currently in various stages of clinical development. New additions to existing antifungal classes will be discussed, including SUBA-itraconazole, a highly bioavailable azole, and amphotericin B cochleate, an oral amphotericin formulation, as well as rezafungin, a long-acting echinocandin capable of once-weekly administration. Additionally, novel first-in-class agents such as ibrexafungerp, an oral glucan synthase inhibitor with activity against various resistant fungal isolates, and olorofim, a pyrimidine synthesis inhibitor with a broad spectrum of activity and oral formulation, will be reviewed. Various other innovative antifungal agents and classes, including MGCD290, tetrazoles, and fosmanogepix, will also be examined.

COVID-19 Associated Invasive Pulmonary Aspergillosis: Diagnostic and Therapeutic Challenges

“…Ibrexafungerp, which is structurally similar to echinocandins, inhibits fungal β-1,3-glucan synthase with activity against triazole-resistant Aspergillus sp. Olorofim and fosmanogepix have different novel targets, which are fungal dihydroorotate dehydrogenase, an important enzyme in fungal DNA synthesis, and the inhibition of fungal enzyme Gwt1 inactivating modification of mannoproteins, which is an important component in maintaining fungal cell wall integrity, respectively [ 69 , 70 ]. All three agents have activity against Aspergillus spp., including A. fumigatus, which may impact positively on the future management of patients with IA and more specifically CAPA.…”

The Dynamic Influence of Olorofim (F901318) on the Cell Morphology and Organization of Living Cells of Aspergillus fumigatus

“…Only four classes of antifungal drugs are currently available on the market [3]. Olorofim (formerly known as F901318) is a novel antifungal belonging to a new class of drugs, called the orotomides, that is currently in phase two of clinical development [4][5][6]. Olorofim selectively inhibits the de novo pyrimidine biosynthesis of filamentous fungi by targeting dihydroorotate dehydrogenase (DHODH) [7].…”

Therapies and Vaccines Based on Nanoparticles for the Treatment of Systemic Fungal Infections

“…The drug interacts also with mammalian sterols, such as cholesterol, which can lead to treated patient collateral effects (Carmona and Limper, 2017 ). Azoles are widely prescribed against invasive fungal infections, mainly represented by fluconazole, voriconazole, itraconazole (ITZ), posaconazole, and isavuconazole (Gintjee et al, 2020 ). Azoles act by inhibiting lanosterol 14α-demethylase (Erg11), which converts lanosterol into ergosterol (Di Mambro et al, 2019 ).…”