Structure-Activity Relationship of Polymyxins and Their Interaction with Bacterial Outer Membrane: A Computational Approach

This thesis investigates how polymyxins, a class of last-line antibiotics, interact with bacterial membranes at the atomic level using molecular dynamics simulations. The study shows that even small structural modifications can alter polymyxin conformation and affect their ability to disrupt membranes. Moreover, polymyxin–membrane interactions are also influenced by differences in bacterial membrane composition and by lipid A modifications associated with resistance. Overall, the thesis elucidates the mechanism-based structure–activity relationships of polymyxins and reveals distinct interaction modes across different bacterial membrane environments. These findings provide critical molecular insights to accelerate the development of new antibiotics against life-threatening ‘superbugs’.