Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease

Abstract

SUMMARYFungal infections are on the rise, driven by a growing population at risk and climate change. Currently available antifungals include only five classes, and their utility and efficacy in antifungal treatment are limited by one or more of innate or acquired resistance in some fungi, poor penetration into "sequestered" sites, and agent-specific side effect which require frequent patient reassessment and monitoring. Agents with novel mechanisms, favorable pharmacokinetic (PK) profiles including good oral bioavailability, and fungicidal mechanism(s) are urgently needed. Here, we provide a comprehensive review of novel antifungal agents, with both improved known mechanisms of actions and new antifungal classes, currently in clinical development for treating invasive yeast, mold (filamentous fungi), Pneumocystis jirovecii infections, and dimorphic fungi (endemic mycoses). We further focus on inhaled antifungals and the role of immunotherapy in tackling fungal infections, and the specific PK/pharmacodynamic profiles, tissue distributions as well as drug-drug interactions of novel antifungals. Finally, we review antifungal resistance mechanisms, the role of use of antifungal pesticides in agriculture as drivers of drug resistance, and detail detection methods for antifungal resistance.

Keywords: fungal disease.

Fig 1

Climate change and antifungal use and resistance in agriculture and humans.

Fig 2

Mechanisms underlying antifungal tolerance. Myriad of mechanisms contributes to antifungal tolerance, including genomic plasticity resulting in gene dosage alteration (such as Erg11 and efflux pump upregulation), chaperon activities to restore the protein structure and function of proteins (such as HSP90), mitochondrial loss (such as petite C. glabrata/N. glabratus isolates), and epimutation-mediated gene silencing (such as heterochromatin formation and RNAi-evoked target silencing). Note that core stress responses are not shown here.

Fig 3

Mechanisms generally governing antifungal resistance. Azole resistance involves multiple mechanisms, including the overexpression of efflux pumps (CDR1 and MDR1) due to hyperactive Tac1 and Mrr1, and the overexpression of the drug target using hyperactive UPC2. The drug target mutation is universal for both azole and echinocandin resistance. Mechanisms underpinning AmB resistance have not been shown.

Fig 4

Clinical trials timeline and approval status for novel antifungals.

Fig 5

Indications for novel antifungal drug classes and situations where they might be used off-label.

Fig 6

Promising immunotherapies for invasive fungal disease. Figure showing a selection of components of the antifungal host response, here arbitrarily shown in the setting of invasive aspergillosis. Potential immunotherapeutic agents (divided in cellular, molecular, or vaccination strategies) are depicted, showing their main method of action in the antifungal host response. CAR, chimeric antigen receptor; DC, dendritic cell. Figure created with BioRender.com.

Fig 7

Tissue penetration of new antifungals. CAmB is not displayed: while tissue presentation is thought to mirror that of other AmB formulations, there are no animal data or human data supporting this assumption in the public domain.