Structure, membrane orientation, mechanism, and function of pexiganan — A highly potent antimicrobial peptide designed from magainin

Abstract

The growing problem of bacterial resistance to conventional antibiotic compounds and the need for new antibiotics has stimulated interest in the development of antimicrobial peptides (AMPs) as human therapeutics. Development of topically applied agents, such as pexiganan (also known as MSI-78, an analog of the naturally occurring magainin2, extracted from the skin of the African frog Xenopus laevis) has been the focus of pharmaceutical development largely because of the relative safety of topical therapy and the uncertainty surrounding the long-term toxicology of any new class of drug administered systemically. The main hurdle that has hindered the development of antimicrobial peptides is that many of the naturally occurring peptides (such as magainin), although active in vitro, are effective in animal models of infection only at very high doses, often close to the toxic doses of the peptide, reflecting an unacceptable margin of safety. Though MSI-78 did not pass the FDA approval, it is still the best-studied AMP to date for therapeutic purposes. Biophysical studies have shown that this peptide is unstructured in solution, forms an antiparallel dimer of amphipathic helices upon binding to the membrane, and disrupts membrane via toroidal-type pore formation. This article covers functional, biophysical, biochemical and structural studies on pexiganan.

The chains of the heterodimeric amphibian skin antimicrobial peptide, distinctin, are encoded by separate messenger RNAs

“…This has inspired other researchers to actually engineer disulfide bridges into natural monomeric and linear amphibian skin peptides to form such complexes. Bioassays indeed subsequently confirmed that synthetic heterodimers, such as between magainin 2 and PGLa, and between magainin and its analogue pexiganan (i.e., MSI-78), showed a greatly enhanced antimicrobial activity when compared to the original native (monomeric) peptides [21]. …”

Bactericidal synergy of lysostaphin in combination with antimicrobial peptides

“…25,[32][33][34][35][36][37]. Therefore, synergistic bactericidal activity could result from the peptides having greater access to the cell membrane thanks to the cell wall-degrading abilities of lysostaphin.…”

Membrane interaction of a new synthetic antimicrobial lipopeptide sp-85 with broad spectrum activity

“…They are very diverse in their sequences, length (generally short) and structures (some of them are linear while others are cyclic sometimes due to disulfide bridges, with a variety of secondary structures), but they adopt an amphipathic conformation that allows them to interact and disrupt selectively the negatively charged microbial membranes. No single mechanism can be defined for all AMPs, but despite these differences it can be concluded that they act mainly by binding to membranes and kill bacteria by disrupting membrane packing and organization, causing defects in the membrane with the consequent dissipation of transmembrane potential and leakage of important cellular contents [10][11][12]. In the case of PxB as well as cecropin and other AMPs, the proposed mechanism of action is based on the formation of periplasmic membrane contacts between outer and inner membranes.…”