Antifungal Drug Discovery: The Process and Outcomes

Abstract

New data suggest that the global incidence of several types of fungal diseases have traditionally been under-documented. Of these, mortality caused by invasive fungal infections remains disturbingly high, equal to or exceeding deaths caused by drug-resistant tuberculosis and malaria. It is clear that basic research on new antifungal drugs, vaccines and diagnostic tools is needed. In this review, we focus upon antifungal drug discovery including in vitro assays, compound libraries and approaches to target identification. Genome mining has made it possible to identify fungal-specific targets; however, new compounds to these targets are apparently not in the antimicrobial pipeline. We suggest that ‘repurposing’ compounds (off patent) might be a more immediate starting point. Furthermore, we examine the dogma on antifungal discovery and suggest that a major thrust in technologies such as structural biology, homology modeling and virtual imaging is needed to drive discovery.

Exploiting mitochondria as targets for the development of new antifungals

“…One of the most important developments in drug discovery with a high relevance to antifungal drug discovery has been the increase in chemical genetic and chemical genomic approaches to the identification of new chemical matter and the characterization of new drug targets. 9 Genetic screens for targets (chemobiology) of mutant libraries offer read-outs of loss of tolerance (haploinsufficiency, HI) phenotypes. Or transcriptomics can be used to gain insights into compound mechanism of action.…”

Can repurposing of existing drugs provide more effective therapies for invasive fungal infections?

“…[1] IFIs are of great public health concern with alarmingly high mortality rates because they are difficult to diagnose and often refractory to treatment. [1,2] For example, the mortality rates of the deeply IFIs caused by three among the most common species of human fungal pathogens Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans range between 20% and 40%, 50% and 90%, and 20% and 70%, respectively. [3,4] Successful management of IFIs requires early diagnosis; reversal of underlying predisposing risk factors; surgical debridement, when necessary; and prompt administration of effective antifungal agents.…”

“…Repurposing builds on previous research and development of established medications that have already been tested in humans in terms of toxicology and pharmacology. [2,4,7] Since 2010, by the announcement of the NIH's repurposing initiative by the National Center for Advancing Translational Sciences, the drug-repositioning concept has been expanded, involving considerable interdisciplinary collaboration. [8] The National Cancer Institute/Developmental Therapeutics Program repository maintains approximately >140,000 small molecules and natural products for repurposing evaluation.…”

“…Interestingly, a large number of these compounds have demonstrated activity against pathogenic fungi, including drug-resistant strains. [2] 3. Expert opinion…”

Garcinia xanthochymus Benzophenones Promote Hyphal Apoptosis and Potentiate Activity of Fluconazole against Candida albicans Biofilms

“…Concomitant with increasing drug resistance of C. albicans isolates, there is a dearth of drugs and drug targets for the treatment of systemic candidiasis (9). All current antifungal treatments target an extremely small part of the fungal genome (11). We are searching for new phytochemicals that are involved in protecting plants from fungal infection, realizing that they should have activity against biofilms, a common natural state of fungi.…”