Antimicrobial Peptides (AMPs) are an essential component of the defence system of organisms throughout
nature and they offer protection from invading pathogens. AMPs do not target single defined molecular
structures (epitopes), but act on the cell membrane killing bacteria and fungi rapidly within minutes.
Therefore, as opposed to conventional antibiotics, they are effective regardless of the metabolic activity of
bacteria. In addition to their direct microbicidal activities, these host defence peptides are particularly
attractive because certain peptides show multiple activities such as the regulation of the innate and adaptive
immune systems, inflammation and wound healing, and additional antifungal, antiviral, antiparasitic and
anticancerous activities. AMPs are quite diverse in sequence and secondary structure, but share some
common properties. They are usually short (20-40 amino acids), cationic, amphipathic and exert their
microbicidal effect mostly by compromising the bacterial membrane integrity. Interaction of AMPs with the
anionic membrane surface of the target microbes leads to membrane permeabilization, cell lysis and death.
Experimental observations in model systems were mainly rationalized by the carpet or pore model (Fig. 1).
In the carpet model, AMPs accumulate on the membrane surface oriented in a parallel fashion to the
membrane resulting in local membrane thinning and destabilization of the cell membrane leading to the
release of intracellular content. However, there is compelling evidence that many AMPs also function by a
detergent-like manner, by disrupting the packing and organization of the lipids in a nonspecific way (e.g.
lipid clustering or segregation of polar and nonpolar groups of the lipids) or by inducing non-bilayer lipid
aggregates. Moreover, some AMPs pass the cell membrane and interact with an intracellular target (Fig.1)
leading to loss of bacterial/fungal viability.
Clearly, the mode(s) of action of AMPs differ from that of conventional antibiotics, which often have simple
targets, such as a unique epitope on the cell wall, or in the protein and RNA synthesis processes, allowing the
pathogenic bacteria to develop resistance more rapidly. Furthermore, AMPs are fast-acting and
biodegradable, which alleviates the current concern about residual antibiotics in the environment.
To achieve our goal, novel potent microbicidal agents will be developed that overcome the shortcomings of conventional antibiotics. The unique effect of second generation SAAPs on biofilm infections will be threefold: they will
The basis is the recently developed peptide, OP-145, that shows significant antimicrobial and antibiofilm
properties in vitro. OP-145 has shown to disperse biofilms, kill the bacteria and neutralize their inflammatory
endotoxins1. Moreover, safety and efficacy of OP-145 against BAI has already been demonstrated in chronic
suppurative otitis media Phase I and II clinical trials.
The molecular mechanisms of OP-145 and other peptides interacting with cell membranes will be studied to
unveil the critical structures that account for the desired properties. This knowledge will be used to develop
second generation SAAPs that both disperse and kill biofilm bacteria and fungi and also restrict associated
inflammation that otherwise may result in tissue injury and survival of pathogens.