Antimicrobial Peptide Structure and Mechanism of Action: A Focus on the Role of Membrane Structure

Abstract

Antimicrobial peptides (AMPs) are showing increasing promise as potential candidate antibacterial drugs in the face of the rapidly emerging bacterial resistance to conventional antibiotics in recent years. The target of these peptides is the microbial membrane and there are numerous models to explain their mechanism of action ranging from pore formation to general membrane disruption. The interaction between the AMP and the target membrane is critical to the specificity and activity of these peptides. However, a precise understanding of the relationship between antimicrobial peptide structure and their cytolytic function in a range of organisms is still lacking. This is a result of the complex nature of the interactions of AMPs with the cell membrane, the mechanism of which can vary considerably between different classes of antimicrobia peptides. A wide range of biophysical techniques have been used to study the influence of a number of peptide and membrane properties on the cytolytic activity of these peptides in model membrane systems. Central to characterisation of this interaction is a quantitative analysis of the binding of peptide to the membrane and the coherent dynamic changes in membrane structure. Recently, dual polarization interferometry has been used to perform an in depth analysis of antimicrobial peptide induced membrane perturbation and with new mass-structure co-fitting kinetic analysis have allowed a real-time label free analysis of binding affinity and kinetics. We review these studies which describe multi-step mechanisms which are adopted by various AMPs in nature and may advance our approach to the development of a new generation of effective antimicrobial therapeutics.

Low pH Enhances the Action of Maximin H5 against Staphylococcus aureus and Helps Mediate Lysylated Phosphatidylglycerol-Induced Resistance

“…Across the same pH range, MH5 also showed a strong ability to adopt amphiphilic α-helical structure in the presence of model S. aureus membranes (Figures 3 and 4) and to partition into these membranes ( Figure 5). These observations suggest quite clearly that the activity of MH5 against S. aureus may involve membranolytic action, which is the predominant antimicrobial mechanism employed by AMPs 14,96 . Confirming this suggestion, the peptide exhibited pH dependent lytic action against model S. aureus membranes that appeared to be contingent upon the properties of both the peptide itself and these target membranes (Figures 8 and 9).…”

“…A fundamental requirement in the antimicrobial action of AMPs is the ability to accommodate both the polar and apolar compartments of target microbial cells 14,[94][95][96][97] . Consistent with this ability, MH5 was predicted to adopt amphiphilic α-helical structure in an anisotropic environment ( Figure 1) and has the potential to form a tilted structure as seen for other membrane interactive α-helices 98 .…”

Role of the Cationic C-Terminal Segment of Melittin on Membrane Fragmentation

“…The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 specificity [10][11][12]63 . The stronger affinity of melittin for anionic than for neutral membranes had already been demonstrated [40][41]61 and is corroborated by the present results ( Figure 1).…”

“…It is believed that the cationic charge of CAPs plays a fundamental role in the targeting of bacterial cells [10][11][12] as these typically possess negatively charged membranes 13 . For example, the increase of the net positive charge of synthetic CAPs was found to improve their antimicrobial activity while maintaining low toxicity towards mammalian cells 6,8 .…”

“…Melittin-21Q exhibited a reduced or similar binding to DMPC and to DMPG bilayers compared to native melittin, suggesting a favorable or a limited contribution of the cationic C-terminal portion to membrane affinity. Another investigation, using tryptophan fluorescence, revealed that melittin and its Cterminal truncated versions , and [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], all showed an increased affinity for 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (POPG) 70/30 large unilamellar vesicles (LUVs) compared POPC LUVs 47 (See Supporting Information). These findings highlighted the role of attractive electrostatic interactions.…”