Fungal Lysine Deacetylases in Virulence, Resistance, and Production of Small Bioactive Compounds

Abstract

The growing number of immunocompromised patients begs for efficient therapy strategies against invasive fungal infections. As conventional antifungal treatment is increasingly hampered by resistance to commonly used antifungals, development of novel therapy regimens is required. On the other hand, numerous fungal species are industrially exploited as cell factories of enzymes and chemicals or as producers of medically relevant pharmaceuticals. Consequently, there is immense interest in tapping the almost inexhaustible fungal portfolio of natural products for potential medical and industrial applications. Both the pathogenicity and production of those small metabolites are significantly dependent on the acetylation status of distinct regulatory proteins. Thus, classical lysine deacetylases (KDACs) are crucial virulence determinants and important regulators of natural products of fungi. In this review, we present an overview of the members of classical KDACs and their complexes in filamentous fungi. Further, we discuss the impact of the genetic manipulation of KDACs on the pathogenicity and production of bioactive molecules. Special consideration is given to inhibitors of these enzymes and their role as potential new antifungals and emerging tools for the discovery of novel pharmaceutical drugs and antibiotics in fungal producer strains.

The histone deacetylase Hda1 affects oxidative and osmotic stress response as well as mycoparasitic activity and secondary metabolite biosynthesis in Trichoderma atroviride

“…The mycoparasitic overgrowth of R. solani by the ∆hda1 mutant was severely delayed, whereas B. cinerea could not be completely overgrown. To date, the majority of studies reported on a critical impact of the class I HDAC Hos2 on virulence or pathogenicity in other fungi ( 10 , 11 ), and, consistent with our findings, the class II HDAC Hda1 was also described as virulence determinant in some species. In Cryptococcus neoformans , Hda1 is a central mediator of virulence ( 49 ); in the plant pathogen M. oryzae , hda1 gene deletion caused a 60% reduction of lesions ( 50 ); and in F. fujikuroi , a 25% reduction of internode elongation in the host plant Oryza sativa was reported ( 21 ).…”

“…“Classical”—Zn 2+ ion binding—fungal lysine deacetylases can be assigned to class I (Rpd3 family comprising the enzymes Rpd3 and Hos2) and class II (Hda1 family comprising the enzymes Hda1 and Hos3) HDACs, based on their sequence similarity to the respective Saccharomyces cerevisiae orthologues ( 11 – 15 ). Functional characterization of the class I HDAC Hda-2 in T. atroviride —the orthologue of S. cerevisiae Hos2—was described to regulate growth, conidiation, blue light perception, and oxidative stress response ( 16 ).…”

Potential antifungal targets based on histones post-translational modifications against invasive aspergillosis

“…Histone deacetylation is the most widely studied among fungal epigenetic modifications ( Bauer and Graessle, 2021 ). HDACs are important in eukaryotic cells which play an essential role in gene expression, transcription and post-transcriptional protein modification by reducing the acetylation level of histones.…”

BET–HDAC Dual Inhibitors for Combinational Treatment of Breast Cancer and Concurrent Candidiasis

“…When used in combination with FLC, HDAC inhibitors 1 , TSA, and MGCD290 significantly improved the sensitivity of FLC against resistant C. albicans isolates by reducing the expression of ERG3, ERG11 (encoding azole targets), and CDR/MDR1 (encoding multidrug transporters) genes. − …”