The limitless endophytes: their role as antifungal agents against top priority pathogens

Abstract

Multi resistant fungi are on the rise, and our arsenal compounds are limited to few choices in the market such as polyenes, pyrimidine analogs, azoles, allylamines, and echinocandins. Although each of these drugs featured a unique mechanism, antifungal resistant strains did emerge and continued to arise against them worldwide. Moreover, the genetic variation between fungi and their host humans is small, which leads to significant challenges in new antifungal drug discovery. Endophytes are still an underexplored source of bioactive secondary metabolites. Many studies were conducted to isolate and screen endophytic pure compounds with efficacy against resistant yeasts and fungi; especially, Candida albicans, C. auris, Cryptococcus neoformans and Aspergillus fumigatus, which encouraged writing this review to critically analyze the chemical nature, potency, and fungal source of the isolated endophytic compounds as well as their novelty features and SAR when possible. Herein, we report a comprehensive list of around 320 assayed antifungal compounds against Candida albicans, C. auris, Cryptococcus neoformans and Aspergillus fumigatus in the period 1980-2024, the majority of which were isolated from fungi of orders Eurotiales and Hypocreales associated with terrestrial plants, probably due to the ease of laboratory cultivation of these strains. 46% of the reviewed compounds were active against C. albicans, 23% against C. neoformans, 29% against A. fumigatus and only 2% against C. auris. Coculturing was proved to be an effective technique to induce cryptic metabolites absent in other axenic cultures or host extract cultures, with Irperide as the most promising compounds MIC value 1 μg/mL. C. auris was susceptible to only persephacin and rubiginosin C. The latter showed potent inhibition against this recalcitrant strain in a non-fungicide way, which unveils the potential of fungal biofilm inhibition. Further development of culturing techniques and activation of silent metabolic pathways would be favorable to inspire the search for novel bioactive antifungals.

Keywords: Antifungal; Coculture; Endophytes; Fungal biofilm; Multi-resistant fungi.

Fig. 1

Endophytic terpene compounds with antifungal potential activity

Fig. 2

Endophytic alkaloids with antifungal potential activity

Fig. 3

Endophytic peptides and amides with antifungal potential activity

Fig. 4

Endophytic polyketides with antifungal potential activity

Fig. 4

Endophytic polyketides with antifungal potential activity

Fig. 4

Endophytic polyketides with antifungal potential activity

Fig. 5

Endophytic miscellaneous compounds with antifungal potential activity

Fig. 6

Percentage of endophytic isolated compounds with promising activity against selected priority pathogens (total 101 compounds)

Fig. 7

Endophytic fungal diversity with potential antifungal effect against selected priority pathogens. (Y-axis: number of endophytic fungal strains with antifungal activity against selected strains, X-axis: diversity of the endophytic fungal strains)

Fig. 8

Marine endophytic compounds with potential antifungal activity against selected priority pathogens

Fig. 9

Coculture endophytic compounds with potential antifungal activity against selected priority pathogens

Fig. 10

Endophytic compounds with potential biofilm inhibitory activity against selected priority pathogens