Hiroshi Nikaido reviews the molecular basis of bacterial outer membrane (OM) permeability, focusing on protein channels and their roles in nutrient transport and antibiotic resistance. The OM, a lipid bilayer, acts as a selective permeability barrier, with porins being key proteins that allow the diffusion of hydrophilic solutes. Porins are found in gram-negative bacteria and some gram-positive species, forming non-specific channels. Classical porins like OmpF, OmpC, and PhoE have been extensively studied, with OmpF being the major porin in P. aeruginosa. These porins have distinct preferences for solute charge and size, with OmpF allowing larger solutes than OmpC. Crystallographic studies have revealed that porins form β-barrel structures, with the eyelet region playing a critical role in channel narrowing. Functional assays, including single-channel conductance and liposome-swelling experiments, have provided insights into porin size and function. However, single-channel conductance measurements can be misleading due to the trimeric nature of porins. The OM's asymmetric bilayer, with lipopolysaccharides (LPS) in the outer leaflet, contributes to its permeability barrier. Porin expression is regulated by environmental factors such as osmolarity, temperature, and pH, with OmpF and OmpC showing distinct expression patterns. Mutations in porins can alter channel size and function, affecting permeability. Voltage-gating of porins has been observed, but its physiological significance remains debated. Porin function is also influenced by polyamines, which can close channels and affect antibiotic resistance. Overall, the study highlights the complexity of OM permeability and the importance of porins in bacterial physiology and antibiotic resistance.Hiroshi Nikaido reviews the molecular basis of bacterial outer membrane (OM) permeability, focusing on protein channels and their roles in nutrient transport and antibiotic resistance. The OM, a lipid bilayer, acts as a selective permeability barrier, with porins being key proteins that allow the diffusion of hydrophilic solutes. Porins are found in gram-negative bacteria and some gram-positive species, forming non-specific channels. Classical porins like OmpF, OmpC, and PhoE have been extensively studied, with OmpF being the major porin in P. aeruginosa. These porins have distinct preferences for solute charge and size, with OmpF allowing larger solutes than OmpC. Crystallographic studies have revealed that porins form β-barrel structures, with the eyelet region playing a critical role in channel narrowing. Functional assays, including single-channel conductance and liposome-swelling experiments, have provided insights into porin size and function. However, single-channel conductance measurements can be misleading due to the trimeric nature of porins. The OM's asymmetric bilayer, with lipopolysaccharides (LPS) in the outer leaflet, contributes to its permeability barrier. Porin expression is regulated by environmental factors such as osmolarity, temperature, and pH, with OmpF and OmpC showing distinct expression patterns. Mutations in porins can alter channel size and function, affecting permeability. Voltage-gating of porins has been observed, but its physiological significance remains debated. Porin function is also influenced by polyamines, which can close channels and affect antibiotic resistance. Overall, the study highlights the complexity of OM permeability and the importance of porins in bacterial physiology and antibiotic resistance.