Targeting the Candida albicans agglutinin-like sequence 3 adhesin to disrupt oral polymicrobial bacterial-fungal biofilms: mechanisms and therapeutic strategies.

Abstract

Oral polymicrobial biofilms formed between Candida albicans and bacterial pathogens underlie early childhood caries, denture stomatitis, periodontal disease, and oropharyngeal candidiasis, infections that conventional antimicrobials consistently fail to eradicate. The agglutinin-like sequence 3 (Als3) protein is a GPI-anchored hypha-specific adhesin that serves as the principal molecular scaffold for interkingdom co-aggregation in these biofilms. This review examines the molecular architecture and domain organization of Als3, including the N-terminal peptide-binding cavity (PBC) and the amyloid-forming region, as well as the regulatory network controlling ALS3 expression. The structural basis of Als3 interactions with staphylococcal MSCRAMMs, streptococcal antigen I/II adhesins, Porphyromonas gingivalis internalin InlJ, and Streptococcus mutans glucosyltransferases is examined in detail. Emergent properties of Als3-dependent oral co-biofilms, including elevated antimicrobial tolerance, architectural complexity, metabolic interdependence, and interkingdom signaling amplification, are analyzed. Therapeutic strategies reviewed include the NDV-3A recombinant vaccine, anti-Als3 monoclonal antibodies, peptide-based competitive inhibitors, and small-molecule antagonists that bind the Als3 N-terminal domain. Als3 acts at the interface between bacteria and fungi. Because of this, it is one of the few targets for which a single treatment can act on both the fungal and bacterial components of these hard-to-treat oral biofilms at once.