Mycobcaterial cell wall is unique, thick waxy and hydrophobic in nature, which ensures its survival inside human macrophages by resisting oxidative damages.The waxy, highly impermeable nature of the wall provides the required defense mechanism against antibiotic agents, and the host organisms. A key component of the cell wall is mycolic acids. Mycolic acid accounts up to 60% of the dry weight of the organisms which means that most percentage of mycobacteria is a cell wall. Thorough understanding of the influence of polarity on the drug penetration in to highly impermeable mycobacterial cell wall will guide us to improve permeability.
The permeation ability of a lipophilic molecule is inversely related to the fluidity of the cell wall, which decreases as the length of fatty acids in the mycolic acids layer increases. The permeability barrier presented by this cell envelope is also thought to be a reason why many common antibiotics are ineffective against mycobacteria. Lipophilic drugs, such as fluoroquinolones or rifamycins, pass more easily through the lipid-rich cell wall and thus are more active.
It is clear that, depending on the library screens towards compounds with a particular physicochemical parameter could actually be detrimental and decrease the diversity of finding new anti-TB drugs.