Module 2: New Approaches (Novozymes, uBonn, uTrieste)
Antimicrobial peptides (AMPs) are among the most promising new antimicrobials. The AMPs are relatively short polypeptide species, ranging from a dozen to over 50 amino acids, with typically a net prevalence of basic residues and over a third hydrophobic residues. This results in cationic, amphipathic structures that can interact well with anionic microbial membranes. AMP structures are otherwise quite varied, and can be linear α-helical, β-sheet, β-hairpin, cyclic, or elongated (Figure 3). Furthermore, these amphipathic structures can be preformed, or form only in association with membranes. Many AMPs thus act by interacting with, and some-how disrupting, the microbial membrane, and/or by subsequently translocating to and interfering with internal or external metabolic targets. In some cases, membrane binding appears to be driven mainly by an initial electrostatic interaction with anionic phospholipids, of which bacterial membranes are particularly rich, while in others it involves binding with specific lipid components leading to a more specific inactivation mechanism. At least one class of animal AMPs, the proline-rich peptides (PRPs) found in some mammals and insects, appears to translocate into the bacterial cytoplasm using specific protein transport systems, and then hit internal molecular targets.
Apart from a direct antimicrobial activity, many cationic AMPs have been shown to also have immunomodulary activities, i.e. they can function by fortifying the immune system after interacting with host immune cells. Therefore, these endogenous antibiotics are both multimodal (many ways of directly inactivating pathogens) and multifunctional (direct and immunostimulatory activities). Animals, including mammals, can have dozens of different AMPs, which likely have overlapping antimicrobial and immunomodulatory activities. The multifunctionality of host defense AMPs is considered an important reason why these ubiquitously endogenous antibiotics managed to remain active throughout evolution, unlike the highly potent man-made antibiotic drugs (Peschel and Sahl 2006). The elucidation of the principles governing the evolution and the activities of AMPs is very likely to provide a basis for the design of entirely novel anti-infective strategies. Proof-of principle has been reported recently when it was demonstrated that synthetic AMPs, designed to have little or no antibiotic but strong immunostimulatory activity, provided excellent protection in various infectious disease animal models.
The complexity of AMP activity however means that the mechanisms of antibiotic action (MoAs) of are still largely undefined. The MoAs elucidated to date include
- Inhibition of cell wall formation and/or formation of pores/channels/lesions in the cell membrane leading to disruption of membrane potential and eventual lysis of the cell.
- Interference with components of the bacterial respiratory chain
- Ability to self-translocate into the bacterial cell where they can interfere with vital functions, such as jamming protein synthesis, interacting with DNA or inhibiting nuclease activity (RNase and/or DNase activity).
- Ability to use bacterial transport systems for translocation into the cytoplasm, where they can interfere with vital functions.
