Targeting Unconventional Pathways in Pursuit of Novel Antifungals

Abstract

The impact of invasive fungal infections on human health is a serious, but largely overlooked, public health issue. Commonly affecting the immunocompromised community, fungal infections are predominantly caused by species of Candida, Cryptococcus, and Aspergillus. Treatments are reliant on the aggressive use of pre-existing antifungal drug classes that target the fungal cell wall and membrane. Despite their frequent use, these drugs are subject to unfavorable drug-drug interactions, can cause undesirable side-effects and have compromised efficacy due to the emergence of antifungal resistance. Hence, there is a clear need to develop novel classes of antifungal drugs. A promising approach involves exploiting the metabolic needs of fungi by targeted interruption of essential metabolic pathways. This review highlights potential antifungal targets including enolase, a component of the enolase-plasminogen complex, and enzymes from the mannitol biosynthesis and purine nucleotide biosynthesis pathways. There has been increased interest in the enzymes that comprise these particular pathways and further investigation into their merits as antifungal targets and roles in fungal survival and virulence are warranted. Disruption of these vital processes by targeting unconventional pathways with small molecules or antibodies may serve as a promising approach to discovering novel classes of antifungals.

Drug Resistance and Novel Therapeutic Approaches in Invasive Candidiasis

“…The old agent flucytosine is an under-utilised partner drug in the treatment of invasive candidiasis, including drug-resistant infections. Additional pathways emerging as promising target pathways have been well reviewed elsewhere ( Nguyen et al., 2021 ).…”

Emerging Antifungal Targets and Strategies

“…The review by McCarthy et al [ 42 ] indicated that different structures of fungal cells could be targeted in order to develop novel antifungals including cell wall and cell membrane; but also metabolic pathways (glyoxylate cycle, pyrimidine biosynthesis, cytochrome P450 enzymes, iron metabolism, heme biosynthesis, and acetate metabolism), signal transduction pathways (MAP kinase, PDK1, and calcium signaling), and gene expression [ 42 ]. Some unconventional pathways were also recently proposed as possible targets for the antifungal development: enolase, a part of the enolase-plasminogen complex, along with enzymes involved in the mannitol biosynthesis and purine nucleotide biosynthesis [ 43 ].…”

Selective Metal Chelation by a Thiosemicarbazone Derivative Interferes with Mitochondrial Respiration and Ribosome Biogenesis in Candida albicans

“…Currently used antifungal drugs mainly fall into three major classes: polyenes, azoles, and echinocandins. While echinocandins have a great safety profile, other conventional antifungals, such as amphotericin B, voriconazole (VOR), and itraconazole, possess severe toxicity ( 4 , 5 ). The difficulty of treating fungal infections is further enhanced by the development of resistance to traditional antifungal drugs due to their widespread use.…”