Non-ribosomal Peptides as Structural Determinants of Fungal Hydrophobicity

Three hydrophobic surface binding a proteins link surface hydrophobicity to sporulation, biofilm formation, and host interaction in Mucor lusitanicus

Results show that HsbA proteins in Mucor lusitanicus function as regulators that couple fungal surface remodeling with developmental transitions, thereby coordinating environmental adaptation and host–pathogen interactions.

Fungal Hydrophobins: Taxonomic Distribution, Functional Roles, Physicochemical Properties, and Biotechnological Applications

Hydrophobins are small, cysteine-rich amphipathic proteins predominantly produced by filamentous fungi, known for their ability to self-assemble at hydrophobic–hydrophilic interfaces. These proteins are essential for fungal development, surface interactions, pathogenicity, and environmental adaptation, and they have attracted growing interest for biotechnological applications. In this work, we provide a narrative review of fungal hydrophobins, based on a systematic literature search and manual curation of eligible studies integrated with protein database records from Ascomycota and Basidiomycota. Information was compiled from peer-reviewed publications selected according to predefined eligibility criteria and complemented with UniProt records, covering taxonomic distribution, functional and biophysical properties, and physiological and pathogenic roles. Significant diversity in molecular features and physicochemical profiles was observed, indicating functional specialization across different ecological niches and lifestyles. Additionally, the compiled data highlight various biotechnological applications, such as surface modification, enzyme immobilization, drug delivery systems, biomaterial development, and environmentally sustainable technologies. By consolidating molecular, functional, and applied information across a wide range of fungal species, this review provides a comprehensive reference framework for hydrophobin research and biotechnological innovation.

AtQQS, an Arabidopsis-specific orphan protein, exhibits broad-spectrum antimicrobial activity through membrane disruption.

Plant-derived antimicrobial proteins represent a promising but underexplored source of new anti-infective molecules. In this study, we purified and identified AtQQS (Qua-Quine Starch, NP_189695), a 59-amino-acid orphan protein previously known as a metabolic regulator in Arabidopsis thaliana, and demonstrated direct broad-spectrum antimicrobial activity against bacterial and fungal pathogens. An antimicrobial polypeptide, AtQQS, was purified by C18 reversed-phase high-performance liquid chromatography (RP-HPLC) from A. thaliana plants and confirmed by SDS-PAGE. Recombinant AtQQS protein inhibited the growth of a wide range of pathogens including Gram-negative bacteria, Gram-positive bacteria, yeasts, and phytopathogenic molds, with minimum inhibitory concentrations (MICs) ranging from 8 to 128 μM. The protein also suppressed biofilm formation and reduced pre-formed biofilms of both Escherichia coli and Staphylococcus aureus. Mechanistic investigation using membrane-impermeable fluorescent probes demonstrated that AtQQS exerts its antimicrobial action through membranolytic disruption of both bacterial and fungal cell membranes. AtQQS was well tolerated by normal human keratinocytes (HaCaT) and dermal fibroblasts (HDF) at concentrations that inhibited microbial growth, and it selectively reduced viability of several tumor cell lines. These findings assign a direct antimicrobial function to AtQQS, an activity not previously linked to this orphan protein, and identify it as a structurally compact scaffold for further peptide-based drug development.

A N-methylated antimicrobial peptide targets the fructose transporter FruA of Staphylococcus aureus.

The structural language of fungal cell wall sugars in WHO priority fungi: the determinant of pathogenicity and the gateway to new therapies

Carbohydrates, far beyond their nutritional role, are fundamental biomolecules that encode biological information and mediate critical cellular interactions. In pathogenic fungi, cell wall (CW) glycans serve as both a protective armor and a dynamic interface with the host, directly influencing virulence and immune evasion. This review discusses the intricate architecture and composition of the CW in the four WHO-critical priority fungal pathogens: Aspergillus fumigatus, Candidozyma auris, Cryptococcus neoformans, and Candida albicans. We detail how distinct carbohydrate polymers, including α- and β-glucans, and various mannans, are organized into layered structures that confer mechanical stability, modulate physicochemical properties, and display pathogen-associated molecular patterns (PAMPs). The analysis highlights species-specific adaptations: the conidial “invisibility cloak” and galactosaminogalactan layer of A. fumigatus; the polymorphic mannoprotein outer layer of C. albicans; the unique polysaccharide capsule anchored to the CW in C. neoformans; and the distinct mannan side chains conferring clade-specific traits in C. auris. Given its essentiality and absence in host cells, the fungal CW presents an ideal target for therapeutic intervention. A deep understanding of the biochemical properties and structural complexity of fungal carbohydrates provides critical insights into novel targets for therapeutic intervention, thereby contributing to the rational design of next-generation antifungals and also aiding the development of new therapies through artificial intelligence.

An N-acetylated daropeptide modulates nematode development.

The symbiotic bacterium Photorhabdus is a rich source of bioactive secondary metabolites that mediate tripartite interactions with nematodes and insect hosts. However, natural products of ribosomal origin remain largely underexplored within this ecological niche. Here, we report the identification of aphotorhaptin A, a darobactin-like peptide (daropeptide) natural product from Photorhabdus asymbiotica, which structurally features an ether crosslink and an N-terminal acetyl unit. Biosynthetic investigation uncovers aphotorhaptin A is matured via an unexpected leader cleavage step, and the subsequent N-terminal acetylation confers metabolic stability that maintains the hexapeptide scaffold integrity. Biochemical and structural studies demonstrate the acetyltransferase PasC exhibits remarkable substrate promiscuity, facilitated by an expansive active-site cavity that accommodates diverse acyl-CoA donors and peptide substrates. Unlike the antimicrobial darobactin, aphotorhaptin A appears to lack antibacterial activity but modulates nematode development, and this activity requires the ether crosslink and the N-terminal acetyl group in the hexapeptide scaffold. These findings expand the chemical and biosynthetic space of ribosomal peptide family and establish its link with nematode development and reproduction.