β-barrel membrane proteins have several important biological functions, including transporting water and solutes across the membrane. They are active in the highly hydrophobic environment of the lipid membrane, as opposed to soluble proteins, which function in a more polar, aqueous environment. Globular soluble proteins typically have a hydrophobic core and a polar surface that interacts favorably with water. In the fuzzy oil drop (FOD) model, this distribution is represented by the 3D Gauss function (3DG). In contrast, membrane proteins expose hydrophobic residues on the surface, and, in the case of ion channels, the polar residues face inwards towards a central pore. The distribution of hydrophobic residues in membrane proteins can be characterized by means of 1–3DG, a complementary 3D Gauss function. Such an analysis was carried out on the transmembrane proteins of bacteria, which, despite the considerable similarities of their super-secondary structure (β-barrel), have highly differentiated properties in terms of stabilization based on hydrophobic interactions. The biological activity and substrate specificity of these proteins are determined by the distribution of the polar and nonpolar amino acids. The present analysis allowed us to compare the ways in which the different proteins interact with antibiotics and helped us understand their relative importance in the development of the resistance mechanism. We showed that beta barrel membrane proteins with a hydrophobic core interact less strongly with the molecules they transport.