Phospholipid composition changes in bacterial membranes: A molecular mechanism of antibiotic resistance

The bacterial cell membrane is a structurally essential and relatively accessible target for several antimicrobial agents, including daptomycin, polymyxins, antimicrobial peptides, and polymers. These compounds are often effective against multidrug-resistant bacteria and are considered last resort treatments. While initially considered less prone to resistance development, accumulating evidence shows that bacteria can adapt through various mechanisms - often involving alterations in membrane composition and biophysical properties. Reported resistance mechanisms include changes in phospholipid composition, lipid A structure, membrane fluidity, surface charge, and microdomain organization. Advances in analytical methodologies - including liquid and gas chromatography, capillary electrophoresis, mass spectrometry, and fluorescence-based techniques-have enabled increasingly precise characterization of these adaptations. In this review, we outline membrane remodeling strategies associated with resistance in both Gram-positive and Gram-negative bacteria and provide an overview of analytical methods commonly employed to study these changes. These insights highlight the growing relevance of membrane-level adaptations in antimicrobial resistance and underscore the need for further research using modern lipidomic and biophysical tools.