Targeting bacterial cell envelope stress responses to advance the next generation of antimicrobial approaches

The gram-negative cell envelope represents an essential yet vulnerable structure that maintains cell shape and protects against external threats. Bacteria encounter diverse antimicrobial stresses, prompting cell envelope stress responses (ESRs), which now threaten antimicrobial treatment efficacy owing to their link to antimicrobial resistance (AMR), a major global public health issue frequently associated with increased mortality. Amid recurring foodborne outbreaks, dwindling antibiotic pipelines, and rising AMR risks, innovative approaches to combat bacterial pathogens via envelope-targeting antimicrobial stresses are urgently needed. However, while ESRs and AMR are well-studied in clinical antibiotics and nosocomial environments, their regulatory mechanisms in emerging physical and chemical antimicrobial approaches related to communal environments, such as food systems, are less well studied. This review examines gram-negative ESRs and their connection to AMR, focusing on how the envelope responds to diverse antimicrobial treatments, particularly the emerging physical chemical treatments frequently used in the food systems, and how this knowledge can guide ESR-based interventions. Based on critical analysis of relevant literature, there is a need for future research to prioritize standardized experimental frameworks, integrative multi-omics and functional studies, and bioinformatics-driven mapping of ESR networks to develop predictive models and identify novel targets. From an applied standpoint, synergistic ESR inhibitors and combinatorial physical-chemical approaches should be further explored to enhance the efficacy of foodborne pathogen control.