Antibiotic resistance has emerged as a serious threat in global human health over the last years. Various studies estimate that if no action is taken, we will be soon entering an era when even the most insignificant bacterial infections could lead to prolonged hospitalization or even death. Therefore, there has been an increased effort to discover new antibacterial therapies. One alternative to conventional antibiotics is the use of antimicrobial peptides (AMPs). Various organisms, such as bacteria, plants and humans, produce AMPs as part of their defense mechanism to ward off bacteria. In order to exploit the full potential of AMPs and establish them as new antibiotic agents, a detailed understanding of their bactericidal mechanism of action would be useful. Molecular simulations have been extensively used, to provide a biophysical insight into the behavior of AMPs toward unravelling their complicated mechanism of action.
We focus on AMPs that are produced by bacteria. These are commonly known as bacterocins and have been shown to be effective in the treatment of relevant bacterial infections. We have examined the interactions of Enteroccin A, a class IIa bacteriocin, and Plantaricin EF, a dimeric class IIb bacteriocin, on the presence of a model lipid bilayer that mimics bacterial cell membranes. We have employed atomistic molecular dynamics simulations and enhanced sampling techniques in order to investigate how each of these peptides interacts with the membrane, when they are placed under different initial configurations, such as on the surface or inside the membrane. We finally have simulated mutants of the wild type Plantaricin EF and observed a similar trend between experimental activity and biophysical behavior.
Our simulation results indicate that there are specific groups of residues and motifs that govern the biophysical behavior of the bacteriocins examined. The most important motif is the GxxxG motif, which is also shared among many types of bacteriocins and is hypothesized to be connected with the ability of peptide dimers to penetrate the membrane. We are currently studying the influence of the GxxxG motif on the dimerization process of bacteriocins employing atomistic molecular dynamics simulations and potential of mean force calculations.
We believe that the information yielded from these simulations can provide valuable information for the design and optimization of new antibiotic agents founded on bacteriocins.
See more of this Group/Topical: Computational Molecular Science and Engineering Forum