Antimycotics and fungicides

Whereas multi-resistant bacterial pathogens are very high on the agenda of both the press and funding agencies, relatively little attention is presently being paid to the fact that the number of resistant pathogenic fungi is also on the rise. This topic was treated by Hyde et al. (2018a), we refer to it for the most important and threatening human pathogenic fungal organisms. In fact, there are only a handful of efficient compound classes on the market that are used in antimycotic chemotherapy, including griseofulvin (6), which was already discovered by Grove et al. (1952). The newest class of antimycotics that were launched to the market are the echinocandins (e.g., pneumocandin B0 (7) (Denning 2002). The biosynthesis of these highly complex lipopeptides relies on PKS-NRPS hybrid gene clusters (Chen et al. 2013). They are being produced biotechnologically by large scale fermentation using different fungi that are not phylogenetically related and subsequent semisynthesis. The knowledge about the molecular mechanisms of their biosynthesis may in the future lead to the concise manipulation of the production process that can be directed towards new natural derivatives. Interestingly, a comparative genomics study by Yue et al. (2015) has revealed rather high homologies among the biosynthesis gene clusters of the producer organisms that belong to three different classes of Ascomycota, namely Dothideomycetes, Eurotiomycetes, and Leotiomycetes. Possibly, this has been due to horizontal gene transfer during the evolutionary history of these organisms.

Recent efforts aimed at the discovery of novel antifungal agents have resulted in a number of developmental projects, such as enfumafungin (8) from Hormonema spp. (Pela´ez et al. 2000). This compound class may soon yield the first pharmaceutical drug for use in humans that originated from a fungal endophyte, over 15 years after their first discovery. Even the biosynthesis genes encoding for these unique triterpenoids has only recently been
identified (Kuhnert et al. 2018).

The search for novel antimycotics and fungicides has also resulted in the rediscovery of “old” compounds that may become more interesting in the future because they have originally been found in a screening for agrochemical fungicides and were never evaluated for their effects on human fungal pathogens or their mode of action. While the strobilurins, which are very commercially successful antifungal agents in agriculture (Sauter et al. 1999), have been found inefficient or too toxic for application in humans, many other metabolites with pronounced antifungal effects were apparently never tested on their efficacy against human pathogens. A recent example for such rediscoveries is favolon (9), which is actually a cometabolite of strobilurins produced by the invasive basidiomycete Favolaschia calocera (Chepkirui et al. 2016) and was originally isolated by Anke et al. (1995). Like the sporothriolodes (10) from the xylarialean fungus Hypoxylon monticulosum (Surup et al. 2014; now classified in the new genus Hypomontagnella as H. monticulosa; cf. Lambert et al. 2019), this metabolite shows very strong antifungal effects that are not accompanied by prominent cytotoxicity.