TB Drugs permeability through mycolic acid monolayer: A tale of two force fields

Abstract

Tuberculosis (TB), treatment becomes challenging due to the unique cell wall structure of Mycobacterium tuberculosis (M.tb). Among various components of M.Tb cell wall, mycolic acid (MA) is of particular interest because it is speculated to exhibit extremely low permeability for most of the drug molecules, thus helping M.tb to survive against medical treatment. However, no quantitative assessment of the thermodynamic barrier encountered by various well-known TB drugs in mycolic acid monolayer has been investigated so far using computational tools. On that premise, our present work aims to probe the permeability of some first and second line TB drugs, namely ethambutol, ethionamide, and isoniazid, through the modelled mycolic acid monolayer, with the help of molecular dynamics (MD) simulation, using two set of force field parameters (FF), namely GROMOS 54A7-ATB (GROMOS), and CHARMM36 (CHARMM) FF. Our findings indicate that both FFs provide consistent results in terms of the mode of drug-monolayer interactions but significantly differ in the drug permeability through monolayer. Mycolic acid monolayer generally exhibited a higher free energy barrier of crossing using CHARMM FF, while GROMOS parameters provide better stability of drug molecules on the monolayer surface, due to the greater electrostatic potential at the monolayer-water interface. Although both the FF parameters predicted the highest resistance against ethambutol (permeability value of 8.40×10-34 cm/s and 9.61×10-31 cm/s for CHARMM FF and GROMOS FF, respectively), results using GROMOS were found to be consistent with water solubility of drugs, suggesting it to be a slightly better FF for modelling drug-mycolic acid interactions. Therefore, this study enhances our understanding of TB drug permeability and highlights the potential of GROMOS FF in simulating drug-mycolic acid interactions.