Biofilm state transitions: quorum sensing inhibition and network destabilization.

Biofilms are traditionally viewed as surface-associated, extracellular polymeric substance (EPS)-encased aggregates. Here, we present a theoretical perspective positioning biofilm formation as a coordinated regulatory state transition, drawing on a synthesis of published transcriptomic, proteomic, and metabolic studies that document systemic reprogramming of gene regulatory networks, second-messenger signaling (e.g., cyclic di-GMP), quorum sensing circuits, and metabolic flux distribution. Spatial stratification within biofilms generates metabolically distinct subpopulations-including persisters and dormant cells-that enhance collective robustness. Using Salmonella enterica serovar Typhimurium as a model organism, we formalize quorum sensing inhibition (QSI) as one plausible bifurcation control parameter, with its destabilizing effects described by a coarse-grained phenomenological model governed by cooperativity, population density, and signal decay rates. We show, through bifurcation analysis and cross-referencing with published experimental biofilm disruption studies, that sufficiently strong signal-decay-type QSI can collapse the high-signal biofilm attractor without imposing strong bactericidal pressure. This network-centric perspective elucidates how destabilization of collective regulatory circuits-rather than direct cell killing-can enhance therapeutic susceptibility. Additionally, the framework provides a conceptual basis for combinatorial strategies integrating antivirulence interventions with conventional antimicrobials, with the potential to reduce the pace of resistance evolution by targeting cooperative rather than essential traits. Predictions arising from this framework require direct experimental validation to establish quantitative accuracy. KEY POINTS: • Biofilms can be conceptualized as coordinated regulatory attractor states sustained by multilayered feedback coupling. • QSI is formalized as one plausible bifurcation control parameter capable of destabilizing the high-commitment biofilm state when implemented as signal-degradation-type inhibition. • Network destabilization may enhance antimicrobial susceptibility while imposing lower evolutionary pressure than direct bactericidal approaches.