8. Multimerization of a Proline-Rich Antimicrobial Peptide, Chex-Arg20, Alters Its Mechanism of Interaction with the Escherichia coli Membrane

Summary:

A3-APO, a de novo designed branched dimeric proline-rich antimicrobial peptide (PrAMP), is highly effective against a variety of in vivo bacterial infections. We undertook a selective examination of the mechanism for the Gram-negative Escherichia coli bacterial membrane interaction of the monomer (Chex-Arg20), dimer (A3-APO), and tetramer (A3-APO disulfide-linked dimer). All three synthetic peptides were effective at killing E. coli. However, the tetramer was 30-fold more membrane disruptive than the dimer while the monomer showed no membrane activity. Using flow cytometry and high-resolution fluorescent microscopy, it was observed that dimerization and tetramerization of the Chex-Arg20 monomer led to an alteration in the mechanism of action from non-lytic/membrane hyperpolarization to membrane disruption/depolarization. Our findings show that the membrane interaction and permeability of Chex-Arg20 was altered by multimerization.

Li, W.; O'Brien-Simpson, N. M.; Tailhades, J.; Pantarat, N.; Dawson, R. M.; Otvos Jr, L.; Reynolds, E. C.; Separovic, F.; Hossain, M. A.; Wade, J. D.* (2015): Multimerization of a proline-rich antimicrobial peptide, Chex-Arg20, alters its mechanism of interaction with the Escherichia coli membrane. Chem. Biol. 202, 1250-1258, DOI: 10.1016/j.chembiol.2015.08.011.