Short native antimicrobial peptides and engineered ultrashort lipopeptides: similarities and differences in cell specificities and modes of action

Abstract

Due to the rapid emergence of resistant microbes to the currently available antibiotics, cationic antimicrobial peptides have attracted considerable interest as a possible new generation of anti-infective compounds. However, low cost development for therapeutic or industrial purposes requires, among other properties, that the peptides will be small and with simple structure. Therefore, considerable research has been devoted to optimizing peptide length combined with a simple design. This review focuses on the similarities and differences in the mode of action and target cell specificity of two families of small peptides: the naturally occurring temporins from the skin of amphibia and the engineered ultrashort lipopeptides. We will also discuss the finding that acylation of cationic peptides results in molecules with a more potent spectrum of activity and a higher resistance to proteolytic degradation. Conjugation of fatty acids to linear native peptide sequences is a powerful strategy to engineer novel successful anti-infective drugs.

Antimicrobial Peptides: New Frontiers in the Therapy of Infections

“…Despite toxicity, in 2003 a member of this family, daptomycin, which is active only toward Gram-positive bacteria, has been approved by the FDA in an injection formulation for the treatment of complicated skin and skin structure infections (SSSI) caused by susceptible strains of the following species: S. aureus (including methicillin-resistant strains), Streptococcus pyogenes, S. agalactiae, S. dysgalactiae subspecies equisimilis, and Enterococcus faecalis (vancomycin-susceptible strains only). This example confirms the growing opinion that peptide-based antibiotics will be among the next generation of antiinfective therapy (Mangoni & Shai, 2011). Dalbavancin, oritavancin and telavancin are semisynthetic lipoglycopeptides active against multidrug-resistant Gram-positive pathogens (Zhanel et al, 2010).…”

“…These HDPs are produced by dermal glands, stored within granules and released on the skin surface upon stress, injury, or electrical or norepinephrine stimulation. Their synthesis is induced by contact with microorganisms and is transcriptionally regulated by the NF-jB/IjBa machinery (Mangoni & Shai, 2011). These peptides constitute a rich arsenal of broad-spectrum, cytolytic AMPs characterized by highly variable sequences (Vanhoye et al, 2003).…”

“…Subsequently, many other temporins have been isolated from the secretions of other ranid frogs of both North American and Euroasian origin. At present, the temporin family includes more than 100 members, which share a number of unique properties, such as: i) a short amino acid sequence, that favors cost-efficient chemical synthesis: most temporins are 10-14 amino acid long, with a few 16-17 amino acids exceptions, and an ultrashort temporin of only eight amino acid residues, that represents the smallest naturally occurring linear AMP so far identified, has been isolated from the skin of the frog Phelophylax saharica (Abbassi et al, 2010); ii) a low positive charge ranging from +2 to +3 at neutral pH (in contrast with most AMPs belonging to other families, which usually have a higher net positive charge); iii) high efficiency against a wide range of pathogens, that is retained in serum, and concomitant low or null toxicity to mammalian cells; iv) at least in some cases, immuno-modulatory and/or antiendotoxin activity (Mangoni & Shai, 2011). Temporins exhibit antibacterial, antifungal, antiviral and antiprotozoan activities.…”

“…Most native LiPs consist of a short (six to seven amino acids) linear or cyclic peptide sequence, either positively or negatively charged, with a fatty acid moiety covalently attached to the N-terminus. (Mangoni & Shai, 2011). Both the composition of the peptide moiety and the type of the lipophilic part are sensitive to modifications.…”

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“…AMPs are ubiquitous elements of the innate immune response in a variety of organisms, and most of them included in different databases 6 . They are generally comprising from 10-50 amino acids, and share a cationic character due to prevalence of basic residues, and an amphipathic structure in membrane -mimicking environments 7 .…”