King's College London

Antimicrobial peptides (AMPs) are natural antibiotics, which have gathered a lot of attention because of the need to discover new antibiotics to combat the emergence of resistant organisms. The focus of much research has been to improve our understanding of the mechanism of action of a given AMP to such an extent that we can then improve features of the AMP to increase its bactericidal potency and specificity.  Molecular level detail, explaining the bactericidal potency therefore has the potential to identify the best bactericidal strategies and hence reveal scope for AMP improvement.  

An interdisciplinary team of scientists including members of the research groups of Dr Chris Lorenz (Department of Physics), Dr Alex F Drake (Institute of Pharmaceutical Sciences, IPS) and Dr James Mason (IPS) have combined molecular dynamics simulations with a variety of biophysical experimental methods (including far-UV circular dichroism and solid-state nuclear magnetic resonance (NMR)) to study the interactions between two AMPs, pleurocidin and magainin 2, and the inner membrane of Gram-negative bacteria – this interaction is a key determinant of antibacterial potency. These two AMPs share many physico-chemical properties, however pleurocidin has been found to be ten times more potent towards Gram-negative bacteria than magainin 2. Recently, this interdisciplinary team published a manuscript entitled “Antimicrobial peptide potency is facilitated by greater conformational flexibility when binding to Gram-negative bacterial inner membranes” in Scientific Reports.  This report provides molecular scale detail of the interactions between these two AMPs and a model Gram-negative membrane and, in doing so, demonstrates that structural flexibility is a key feature in the ability of pleurocidin to penetrate deeper into the bacterial membrane than magainin 2, facilitating access to the bacterial cytoplasm and enabling a wider variety of bactericidal effects. 

These findings are now being used to understand and overcome possible bacterial resistance mechanisms while the pleurocidin molecule is being refined, improved and formulated for pre-clinical trials to combat infections from Pseudomonas aeruginosa.