Exploratory transcriptomic analysis of Staphylococcus aureus adaptation during polymicrobial interactions

In the microbial world, survival is not solitary. Staphylococcus aureus thrives or falters depending on its neighbors. This opportunistic pathogen frequently inhabits polymicrobial environments such as chronic wounds, implanted devices, and mucosal surfaces, where interspecies interactions shape its behavior and complicate treatment outcomes. In this study, we adopt an exploratory, systems-level approach to examine how S. aureus transcriptionally adapts during co-culture with three clinically relevant organisms: Pseudomonas aeruginosa , Candida albicans , and Enterococcus faecalis . RNA sequencing uncovered distinct ecological signatures: P. aeruginosa imposed a strongly antagonistic effect, driving global transcriptional repression, including silencing of virulence pathways; C. albicans promoted a synergistic response with activation of virulence, stress, and metabolic genes; while E. faecalis elicited a competitive program characterized by robust induction of the type VII secretion system, cytotoxic effectors, and biosynthetic functions. Rather than definitive mechanisms, these findings provide an exploratory map of interspecies transcriptional landscapes, generating hypotheses on how microbial neighbors modulate S. aureus biology and highlighting interspecies signaling as a potential target for managing polymicrobial infections.