Aspergillus fumigatus biofilms: Toward understanding how growth as a multicellular network increases antifungal resistance and disease progression

Abstract

Aspergillus fumigatus is a saprophytic, filamentous fungus found in soils and compost and the causative agent of several pulmonary diseases in humans, birds, and other mammals. A. fumigatus and other filamentous fungi grow as networks of filamentous hyphae that have characteristics of a classic microbial biofilm. These characteristics include production of an extracellular matrix (ECM), surface adhesion, multicellularity, and increased antimicrobial drug resistance. A. fumigatus biofilm growth occurs in vivo at sites of infection, highlighting the importance of defining mechanisms underlying biofilm development and associated emergent properties. We propose that there are 3 distinct phases in the development of A. fumigatus biofilms: biofilm initiation, immature biofilm, and mature biofilm. These stages are defined both temporally and by unique genetic and structural changes over the course of development. Here, we review known mechanisms within each of these stages that contribute to biofilm structure, ECM production, and increased resistance to contemporary antifungal drugs. We highlight gaps in our understanding of biofilm development and function that when addressed are expected to aid in the development of novel antifungal therapies capable of killing filamentous fungal biofilms.

A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi

“…A. fumigatus biofilm formation is more resistant to antifungal agents (Morelli et al ., 2021). BRI alone at 20 or 40 µM can inhibit about 10 and 60% biofilm formation, respectively (Figure 2C) while VOR alone at 2 µg/ml or 4 µg/ml were able to inhibit about 10 and 50% biofilm formation (Figure 2C); CAS alone at 0.25 µg/ml or 2.0 µg/ml were able to inhibit about 10% biofilm formation (Figure 2C).…”

Filamentous fungal biofilms: Conserved and unique aspects of extracellular matrix composition, mechanisms of drug resistance and regulatory networks in Aspergillus fumigatus

“…Like biofilms in bacteria and yeast, the biofilms of A. fumigatus provide protection from antifungal therapy and host immune defenses 8 , 9 . Recent clinical trials highlight that the mortality of invasive aspergillosis remains as high as 30%, although treatment with the current antifungal agents 10 , 11 .…”

“…The Candida biofilms consisted of a dense network of mixture morphological forms, including yeast cells, hyphae and pseudohyphae 15 . In comparison, interconnected, branched multinucleate vegetative hyphae are the main type of cells within A. fumigatus biofilms 8 . Three-dimensional surface plot analysis has revealed that spatially ordered hyphae, well-structured hyphal channels and vertical hyphal growth are characteristics of the A. fumigatus biofilms 16 , 17 .…”

Understanding the environmental drivers of clinical azole resistance in Aspergillus species

“…This makes it increasingly difficult for immune cells to recognise and influence them. It also worsens when other microbial biofilms persist and are difficult to remove with antifungal drugs, particularly in cystic fibrosis ( 111 ). Therefore, a comprehensive analysis and understanding of Aspergillus biofilms is required to develop new and improved antifungal targets for the treatment of complex biofilm-related diseases ( 107 ).…”