Interactions of isoniazid with membrane models: Implications for drug mechanism of action

•Drug-membrane interaction was assessed using two complementary biophysical tecnhiques.•Drug-membrane interactions were studied under different pH values.•The results point to a higher affinity of the drug to the acidic environments.•This study represent a contribution to the medicinal chemistry and may contribute to the discovery of new drugs.

This work focuses on the application of biophysical techniques to assess the interaction of isoniazid (INH) with three-dimensional cell membrane mimetic models. Liposomes made of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were used as cell membrane lipids, being the interactions of the drug studied under different pH conditions to mimic the in vivo near neutral physiological pH found in the cytoplasm and the acidic conditions encountered in the protective gastric barrier and in the macrophage intracellular acidic compartments (i.e., phagosomes and phagolysomes). The effect of INH on the biophysical parameters of the cell membrane lipids was assessed by dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS). The overall results highlighted the importance of the pH for the interactions of INH with biological membranes. A relationship between the effect of INH on the biophysical properties of the membranes and the pH was established. In fact, the experimental results point to a higher affinity of the drug to the acidic environments, which not only explain its sequestration in the infected cells but also some of its side-effects.