In the past two decades, Antimicrobial peptides (AMPs) have attracted considerable interest because of their potential therapeutic use as... Show moreIn the past two decades, Antimicrobial peptides (AMPs) have attracted considerable interest because of their potential therapeutic use as antibiotics, antivirals, and antitumoural drugs. However, there are a number of serious challenges on the way toward bringing AMPs onto the market which include their rapid in vivo degradation, high production costs, reduced activity in physiological conditions, etc. To overcome these problems and yet to capitalize on the immense potential of AMPs, extensive efforts to develop their non-natural mimics have been recently made. A better understanding of the structure-activity relationships of AMPs is essential to the creation of a successful peptidomimetic compound. It has been widely accepted that AMPs kill pathogens by disrupting the cell membrane or invading the cytoplasm and inhibiting core metabolic functions. Thus, the pathogenic membrane plays a crucial role either as an immediate target or as a barrier that must be traversed. Herein, we have investigated the role of charge and hydrophobicity in the interplay between membrane-active molecules (Oligomers of acyl lysine) and model bacterial or host cell membranes using constant-pressure insertion assays, synchrotron X-ray reflectivity (XR) and grazing incident-angle X-ray diffraction (GIXD). The outer surface of a membrane was approximated by a planar lipid monolayer at the air-liquid interface, whose composition was modified in accordance with the cell being modelled. The presented results have helped us to arrive at a general mechanism by which the OAKs seem to interact with lipids which is strongly dependent upon the charge density of the monolayer, charge and hydrophilicity of the molecule and presence of freely accessible hydrophobic regions. The results indicate the molecules fail to interact with the acyl chains when they poorly negotiate with the head group or when they lack accessible hydrophobic regions. Overall, presented results advance current understanding of the mechanism of action of flexible AMP mimics on bacterial membranes and will no doubt aid in the rational design and optimization of non-natural mimics of antimicrobial peptides that will be effective against multidrug resistant bacteria and cancer cells. Nevertheless, future work is required to further understand the critical factors leading to potent anti-infective activity of antimicrobials. M.S. in Molecular Biochemistry and Biophysics, July 2012 Show less