Interaction of isoniazid derivatives active against drug-resistant tuberculosis with models of the lung surfactant and of the Mycobacterium tuberculosis cell wall.

Tuberculosis is one of the most important causes of death in the world. The emergence and increased prominence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb), non-susceptible to currently available therapies, has toughened the fight to eradicate this disease. This study focuses on further investigating the therapeutic potential of promising antitubercular compounds, namely, isoniazid (INH), and three INH derivatives, N'-decanoylisonicotinohydrazide (INH-C10), N'-(E)-(4-phenoxybenzylidene)isonicotinohydrazide (N34) and N'-(4-phenoxybenzyl)isonicotinohydrazide (N34red). INH-C10 and N34 have been selected due to their high selectivity index against the Mtb mutant bearing the primary mutation responsible for INH drug resistance. In opposition, N34red, which differs from N34 only in the saturation of the N' = C bond, exhibits a poor selectivity index. Moreover, INH-C10 and N34 interact with human serum albumin and model lipid membranes mimicking the plasma membrane of human cells, showing their promising potential. In the current study, the interaction of these compounds with models of the lung surfactant (LS) and of the mycolic acid (MA)-enriched Mtb cell wall was assessed, in order to further explore their ability to interact with and cross the various biological barriers to be encountered on their way to the molecular target inside Mtb. We show that all the INH derivatives were able to interact with both the LS and the mycolic acid-enriched cell wall models. INH-C10 and N34 had a smaller impact than N34red on the pulmonary surfactant model. On the other hand, INH-C10 promoted the most extensive perturbation of the MA-enriched cell wall model, which correlates well with the previously shown ability of this compound to incorporate into and disturb gel-phase lipid bilayers. This indicates that INH-C10 may penetrate a MA rich barrier more easily, reaching higher intracellular levels, and increase its permeability. These traits contribute to explain the high antimicrobial activity of this derivative against the most common drug-resistant Mtb mutant.