Fungal‐Bacterial Interactions in Polymicrobial Infections: Hidden Threats

ABSTRACT Polymicrobial infections involving fungi and bacteria represent a major and increasingly recognized clinical challenge, in which interkingdom interactions significantly amplify disease severity, antimicrobial resistance, and treatment failure. Rather than passive co‐existence, fungal–bacterial communities form highly coordinated systems driven by physical adhesion, quorum sensing, metabolic interdependence, and biofilm‐mediated structural reinforcement. These cooperative interactions, exemplified by pairs such as Candida albicans – Staphylococcus aureus and Pseudomonas aeruginosa – Aspergillus fumigatus , promote the development of treatment‐recalcitrant biofilms with enhanced immune evasion and multidrug tolerance. The global rise of multidrug‐resistant (MDR) and extensively drug‐resistant (XDR) pathogens has further intensified this burden, with polymicrobial biofilms now representing a post‐antibiotic clinical scenario in which therapeutic failure is driven not by individual resistant organisms but by emergent, cooperative resistance architectures. Conventional diagnostic approaches remain insufficient, as culture‐based methods frequently fail to capture the complexity of mixed microbial communities. Emerging technologies such as MALDI‐TOF mass spectrometry, metagenomic sequencing, and fluorescence in situ hybridization offer improved resolution but are not yet fully integrated into routine clinical practice. Therapeutically, increasing evidence indicates that monotherapy is inherently inadequate in polymicrobial infections due to the emergent nature of microbial cooperation. Effective management therefore requires combination strategies that simultaneously target multiple pathogens and their shared biofilm infrastructure. These include antibiotic–antifungal combinations, phage therapy, enzymatic and nanoparticle‐mediated biofilm disruption, metabolic interference, and host‐directed immunomodulation. Importantly, recent advances also highlight the role of biophysical properties such as biofilm viscoelasticity and matrix stiffness as critical and previously underappreciated therapeutic targets. This review uniquely integrates biochemical, biophysical, and therapeutic dimensions of polymicrobial infections into a unified systems‐level framework in which microbial cooperation is the central driver of pathogenesis, resistance, and treatment failure. Fungal–bacterial interactions are thereby positioned along a dynamic continuum from commensalism to pathogenesis, shaped by host susceptibility and environmental perturbations. Future progress will depend on interdisciplinary strategies combining multi‐omics technologies, precision diagnostics, and microbiome‐informed therapeutic design to effectively disrupt these complex microbial networks.