Sterols are essential components of eukaryotic membranes and play a structural role, increasing the resistance of the phospholipid bilayer to various stresses (Evans and Rawicz, 1990; Zhelev and Needham, 1993; Michalak et al., 2013; Hannesschlaeger et al., 2019). Concentrations of sterols are especially high in the plasma membrane, typically comprising 30–40% of the total lipid content (Ejsing et al., 2009; Subczynski et al., 2017). Most prokaryotes lack sterol biosynthesis machinery and thus their plasma membranes are sterol-free. Many antimicrobial drugs disrupt the plasma membrane phospholipid bilayer. Here we ask whether antifungal and antibacterial compounds are fundamentally different in their physico-chemical properties which reflect their interactions with plasma membranes with distinct lipid compositions. A drug-membrane interaction can be divided into two stages: first, a drug moves from the aqueous phase into the water-membrane interface saturated by polar and charged groups. Next, it penetrates into the hydrophobic core of the phospholipid bilayer. Thus, we estimated the energy costs of these two steps for the antibacterial and antifungal compounds commonly used for medical and/or agricultural purposes. We have deliberately limited our analysis to such practically used compounds because their biological activities are, obviously, characterized more thoroughly than the ones of the chemicals used, for instance, for research purposes only. It appeared that while antibacterial compounds differed considerably in terms of the energy costs, antifungal compounds displayed a significant degree of similarity. This finding suggests a common mechanism for the interaction between the antifungal membrane-active compounds and the fungal plasma membrane.