Molecular design of antimicrobial peptides based on
hemagglutinin fusion domain to combat antibiotic resistance in
Center of infectious Diseases, West China
Hospital, Sichuan University, Chengdu
Hui Ye, Center of infectious Diseases, West
China Hospital, Sichuan University, Chengdu
Antimicrobial peptides are derived from the viral fusion domain of influenza virus hemagglutinin
based on rational analysis of the intermolecular interaction between peptides and bacterial outer
membrane. It is revealed that the isolated viral fusion domain is a negatively charged peptide
that cannot effectively interact with the anionic membrane. Conversion of the native
to a positively charged peptide HAfp
_KK by E11K/D19K mutation can promote
the peptide‐membrane interaction substantially; this confers to the peptide a moderate antibac-
terial potency against antibiotic‐resistant bacterial strains. Cyclization of the linear peptide
_KK results in a cyclic peptide cHAfp
_KK, which can largely minimize entropy pen-
alty upon the peptide‐membrane binding by pre‐stabilizing peptide hairpin configuration in sol-
vent, where the linear peptide would incur in a considerable conformational change/folding
from intrinsic disorder (in water) to the structured hairpin conformation (in lipid). As might be
expected, the cyclization considerably improves peptide antibacterial activity with minimum
inhibitory concentration of 67 and 34 μg/mL against multidrug‐resistant Pseudomonas aeruginosa
and methicillin‐resistant Staphylococcus aureus, respectively.
antibiotic resistance, antimicrobial peptide, bacterial infection, membrane activity, structural
dynamics, viral fusion domain
Antimicrobial resistance (AMR) within a wide range of anti‐infective
agents is a growing public health threat of broad concern to countries
and multiple sectors.
The rapid emergence of resistant bacteria is
occurring worldwide, endangering the efficacy of antibiotics, which
have transformed medicine and saved millions of lives.
new classes of antibiotics has long been great attraction in the medi-
Many efforts have been directed toward finding
alternative antibiotics unaffected by resistance mechanisms. Antimi-
crobial peptides (AMPs) are regarded as one of the most promising
alternatives in this regard.
AMPs are membrane‐active peptides
with excess cationic residues and wide hydrophobic patches.
They fall into 4 major structural categories based on their amphiphilic
conformations that are preformed or occur after membrane interac-
tion, that is, α‐helix, β‐sheet, loop coil, and extended configuration.
New strategies have been developed to identify and discover
AMPs with high antibacterial potency against multidrug‐resistant
pathogens in clinical practice.
Previous studies demonstrated that the
viral fusion domains (VFDs), another class of MAPs as an important
component of viral capsid structural proteins,
can be used as structural
templates to design AMPs
; AMPs have been successfully derived from
the VFDs of influenza A virus
and chikungunya virus.
known that there is a considerable difference between AMPs and VFDs
as the chemical compositions and physical properties of bacterial outer
membranes and mammalian cell membranes are quite different.
addition, many VFDs act generally at the intracellular side of the mem-
brane to produce cell permeabilization and lysis. The inner membrane
leaflet has a different lipid composition in respect to the outer one,
and these fusion domains are therefore evolved to insert in this leaflet
and act on eukaryotic cells. This is an important difference between
the peptide‐membrane interaction of AMPs and VFDs.
In the current work, we performed molecular simulation and con-
formational analysis to characterize the structural basis and dynamics
property of influenza hemagglutinin VFDs and to investigate its inter-
action with the lipid bilayer models of both bacterial and mammalian
Received: 11 November 2017 Revised: 15 January 2018 Accepted: 15 January 2018
J Pep Sci. 2018;24:e3068.
Copyright © 2018 European Peptide Society and John Wiley & Sons, Ltd.wileyonlinelibrary.com/journal/psc 1of9