Pexiganan (MSI-78)

Overview

Magainins are host-defence peptides first isolated from Xenopus laevis skin. Through structure-activity optimisation, pexiganan was engineered from magainin 2 for enhanced potency and stability as a topical agent. Like other cationic amphipathic peptides, it kills bacteria by physically disrupting their membranes rather than acting on a specific protein target.

In a phase 3 trial, pexiganan cream produced clinical improvement and microbiological eradication rates comparable to oral ofloxacin in mildly infected diabetic foot ulcers, without promoting resistant organisms. However, because it did not demonstrate superiority to placebo plus wound care in later confirmatory studies, pexiganan has not received FDA approval and remains investigational.

As a broad-spectrum, rapidly bactericidal peptide with a membrane-lytic mechanism, pexiganan is often cited as a proof-of-concept for topical antimicrobial-peptide therapeutics against increasingly resistant wound pathogens.

Mechanism of Action

The peptide's positive charge draws it to negatively charged bacterial surfaces (rich in phosphatidylglycerol and, in Gram-negatives, LPS), while its amphipathic helix partitions into the membrane. Accumulation thins and permeabilises the bilayer via a carpet/toroidal-pore mechanism, dissipating ion gradients within minutes. Because killing depends on membrane physicochemistry rather than a single mutable target, resistance develops slowly.

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