Lipidome plasticity and envelope remodeling under environmental stress in Gram-negative bacteria

Gram-negative bacterial cell envelopes comprise complex lipid components essential for survival and virulence, functioning as a dynamic barrier against environmental stress. Beyond canonical biosynthetic pathways, Gram-negative bacteria employ multiple adaptive strategies to preserve envelope integrity under nutrient limitation and host-imposed pressures. These include stress-induced lipid remodeling processes such as headgroup substitution, acyl-chain modification, and host lipid-driven membrane incorporation through phosphatidylcholine biosynthesis and the assimilation of host-derived fatty acids, thereby reshaping membrane composition, biophysical properties, and antibiotic susceptibility. Recent biophysical and imaging studies indicate that variable lipidome adaptation to stress drives the spatial clustering of lipids and membrane proteins, forming functional microdomains that regulate membrane permeability, efflux activity, and envelope mechanics. Adaptive reorganization of membrane lipids can facilitate vesiculation and selectively alter membrane permeability to antibiotics and antimicrobial peptides by generating leaflet imbalances that induce localized curvature and lateral pressure heterogeneity. Targeting these lipid remodeling pathways represents a promising therapeutic approach that could sensitize resistant pathogens and guide the development of effective adjuvant strategies.