Breaking down biofilms across critical priority fungal pathogens: proteomics and computational innovation for mechanistic insights and new target discovery

Abstract

Fungal biofilms are complex microbial structures associated with persistent and progressive infections, such as cryptococcal meningitis, invasive aspergillosis, and invasive candidiasis, leading to thousands of deaths annually. The prevalence of fungal biofilm formation during infections, with its heightened resistance to antifungal drugs, highlights the urgency for the discovery and development of new antifungals with antibiofilm activity. Current advances in mass spectrometry-based proteomics and computational platforms provide a powerful toolkit to accelerate drug discovery from target identification to optimization of a lead molecule. In this review, we highlight fungal biofilms of four critical priority fungal pathogens (as deemed by the World Health Organization) and define important technological considerations for proteomics and computational methodologies. Additionally, we explore recent proteomics and computational applications within fungal biofilms for the identification and elucidation of biological mechanisms underscoring biofilm formation as well as the discovery of novel putative antibiofilm targets.

Keywords: biofilms; computational methods; critical priority fungal pathogens; drug discovery; mass spectrometry-based proteomics.

Fig 1

Biofilm formation as a mechanism of infection by C. neoformans, A. fumigatus, and C. albicans. Cryptococcoma formation is initiated by cryptococci crossing the blood-brain barrier through different mechanisms (i.e., paracellular transmigration). Once in the brain, the yeast cells attach to a surface, forming a basal layer, followed by the extracellular polysaccharide matrix secretion. For A. fumigatus, after inhalation, the conidia may lodge in pre-existing cavities caused by previous diseases in lung tissue, where they germinate, and after hyphae formation, an EPM is produced, gluing the filaments together and producing a fungal ball (aspergilloma). C. albicans can colonize biotic and abiotic surfaces through biofilm formation, with yeast cells forming an initial basal layer to undergo a morphological switch to hyphae for the production of EPM.

Fig 2

Mass spectrometry-based proteomics and computational methods applicable in the drug discovery process. MoA, mechanism of action.