Lysine acetylation as drug target in fungi: an underexplored potential in Aspergillus spp.

Abstract

In recent years, the intensification of the use of immunosuppressive therapies has increased the incidence of invasive infections caused by opportunistic fungi. Considering that, the spread of azole resistance and amphotericin B (AmB) inefficiency against some clinical and environmental isolates has been described. Thus, to avoid a global problem when controlling fungal infections and critical failures in medicine, and food security, new approaches for drug target identification and for the development of new treatments that are more effective against pathogenic fungi are desired. Recent studies indicate that protein acetylation is present in hundreds of proteins of different cellular compartments and is involved in several biological processes, i.e., metabolism, translation, gene expression regulation, and oxidative stress response, from prokaryotes and eukaryotes, including fungi, demonstrating that lysine acetylation plays an important role in essential mechanisms. Lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), the two enzyme families responsible for regulating protein acetylation levels, have been explored as drug targets for the treatment of several human diseases and infections. Aspergilli have on average 8 KAT genes and 11 KDAC genes in their genomes. This review aims to summarize the available knowledge about Aspergillus spp. azole resistance mechanisms and the role of lysine acetylation in the control of biological processes in fungi. We also want to discuss the lysine acetylation as a potential target for fungal infection treatment and drug target discovery.

Molecular targets for antifungals in amino acid and protein biosynthetic pathways

“…Majority of eukaryotic proteins undergo reversible post-translational modifications (PTM) that enable them to gain their final activity. These processes include acetylation, methylation, phosphorylation, glycosylation, and ubiquitination of protein molecules (Wassano et al 2020 ). Reversible PTMs control various cell processes via regulation of protein function, the most important modification is acetylation of proteins that regulates translation, gene expression, and metabolism (Kuchler et al 2016 ).…”

“…Acetylation is an evolutionarily conserved process that involves acetyltransferase enzymes transmitting the acetyl group from a donor acetyl coenzyme A (CoA) to a suitable acceptor molecule. Histone acetyltransferases EC 2.3.1.48 (HATs) and histone deacetylases EC 3.5.1.98 (HADC) catalyze, respectively, the addition or removal of acetyl groups to or from lysine residues, most importantly in histone proteins, and have been identified as potential drug targets (Wassano et al 2020 ). It was revealed that HAT/ HADC activities are required for C. albicans virulence.…”

Protein acetylation and deacetylation in plant‐pathogen interactions

“…Currently, several KAT and KDAC inhibitors have been developed for the treatment of fungal infections in humans. For example, nicotinamide is widely used as an overall sirtuin inhibitor (Avalos et al ., 2005), which strongly suppresses the growth of various pathogenic fungi, such as Candida albicans , Candida krusei , Aspergillus fumigatus and Aspergillus nidulans (Wurtele et al ., 2010; Wassano et al ., 2020). In addition, anacardic acid (6‐pentadecylsalicylic acid), a KAT inhibitor that inhibits p300, PCAF and Tip60, also affects the mycelial growth and conidial germination of the plant‐pathogenic fungus M. oryzae (Muzaffar et al ., 2016).…”

Post-translational modifications confer amphotericin B resistance in Candida krusei isolated from a neutropenic patient

“…Post-translational modifications (PTMs) have also attracted attention because of their vital roles in fungal growth, virulence, stress responses, and drug resistance (20,21). Increasing evidence indicates that PTMs, especially acetylation, contribute to the development of drug resistance in different fungi (22,23). However, no study has considered the role of PTMs in the development of drug resistance in C. krusei.…”