The antifungal pipeline: a reality check

Abstract

Invasive fungal infections continue to appear in record numbers as the immunocompromised population of the world increases, owing partially to the increased number of individuals who are infected with HIV and partially to the successful treatment of serious underlying diseases. The effectiveness of current antifungal therapies — polyenes, flucytosine, azoles and echinocandins (as monotherapies or in combinations for prophylaxis, or as empiric, pre-emptive or specific therapies) — in the management of these infections has plateaued. Although these drugs are clinically useful, they have several limitations, such as off-target toxicity, and drug-resistant fungi are now emerging. New antifungals are therefore needed. In this Review, I discuss the robust and dynamic antifungal pipeline, including results from preclinical academic efforts through to pharmaceutical industry products, and describe the targets, strategies, compounds and potential outcomes.

Identification of cyclosporin C from Amphichorda felina using a Cryptococcus neoformans differential temperature sensitivity assay

“…Implementation of an economical screening method is critical for high-throughput discovery and lead optimization studies. Furthermore, the assay may detect compounds that inhibit alternative pathways and targets involved in thermal adaption in C. neoformans , including Ras-mediated signaling pathways and trehalose biosynthesis (Esher et al 2016; Perfect 2017). …”

“…Current therapies for this disease include a limited number of antifungal agents (amphotericin B, flucytosine, and fluconazole). Despite the emergence of drug-resistant strains (Smith et al 2015), no new therapies for this condition have been introduced in the past few decades (Coelho and Casadevall 2016; Perfect 2017). …”

Riboflavin and pantothenic acid biosynthesis are crucial for iron homeostasis and virulence in the pathogenic mold Aspergillus fumigatus

“…Second, inhibition of a single cellular target often results in mutations leading to resistance. Nevertheless, these problems can be circumvented by developing inhibitors that (i) react with the target enzyme to generate toxic products or (ii) block additional essential fungal targets, and (iii) by using drug combinations [3]. …”

“…Despite modern antifungal treatments, mortality rates remain between 20 to 90%. Treatment efficacy has plateaued and fungal resistance is developing [3]. …”

Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis

“…Aspergillus are primarily responsible for pulmonary infections in immunocompromised patients including those receiving solid organ transplants 9 . The challenge posed by pathogenic fungi continues to remain an ongoing global problem both in resource-limited regions (where few antifungal drugs are available for use) and developed nations where aggressive treatments for other diseases (such as cancer) may predispose susceptible patients to invasive fungal infections 10 .…”