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J Appl Microbiol. 2021;00:1–24. wileyonlinelibrary.com/journal/jam
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© 2021 Society for Applied Microbiology
INTRODUCTION
The World Health Organization (WHO) reports that an-
tibiotic resistance continues to increase worldwide and
therefore warns that a period in which infections can no
longer be treated with antibiotics is approaching (Xie et al.,
2017). The increase in antibiotic- resistant bacterial strains
has caused the need for the development of new antimi-
crobial agents that can be used in treatment (Neubauer
et al., 2017). In recent years, epidemics and pandemics
have revealed that public health is potentially under a
global threat in terms of infectious diseases and the need
for new and effective antimicrobial agents in combating
new emerging microbial diseases continues.
Aquatic or terrestrial invertebrates can protect them-
selves against pathogenic microorganisms in their natu-
ral environment, although they do not have any adaptive
immune system. These organisms overcome infections
caused by pathogenic microorganism through antimicro-
bial peptides (AMPs) that are naturally produced by their
innate immune defence system (Brogden, 2005; Gueguen
et al., 2009).
AMPs are potential multifunctional therapeutic
agents, which are effective for a broad spectrum of
microorganisms. They are called ‘natural antibiotics’.
Some AMPs can cause rapid death in Gram- positive,
Gram- negative, fungi, parasites, encapsulated viruses
or tumour cells within a few minutes. AMPs have a
Received: 7 August 2020
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Revised: 26 August 2021
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Accepted: 17 September 2021
DOI: 10.1111/jam.15314
REVIEW ARTICLE
Antimicrobial peptides (AMPs): A promising class of
antimicrobial compounds
MineErdem Büyükkiraz1
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ZülalKesmen2
1School of Health Sciences, Department
of Nutrition and Dietetics, Cappadocia
University, Nevsehir, Turkey
2Engineering Faculty, Department of
Food Engineering, Erciyes University,
Kayseri, Turkey
Correspondence
Zülal Kesmen, Engineering Faculty,
Department of Food Engineering,
Erciyes University, Kayseri, Turkey.
Email: zkesmen@erciyes.edu.tr
Abstract
Antimicrobial peptides (AMPs) are compounds, which have inhibitory activity
against microorganisms. In the last decades, AMPs have become powerful alterna-
tive agents that have met the need for novel anti- infectives to overcome increasing
antibiotic resistance problems. Moreover, recent epidemics and pandemics are in-
creasing the popularity of AMPs, due to the urgent necessity for effective antimicro-
bial agents in combating the new emergence of microbial diseases. AMPs inhibit a
wide range of microorganisms through diverse and special mechanisms by targeting
mainly cell membranes or specific intracellular components. In addition to extrac-
tion from natural sources, AMPs are produced in various hosts using recombinant
methods. More recently, the synthetic analogues of AMPs, designed with some mod-
ifications, are predicted to overcome the limitations of stability, toxicity and activity
associated with natural AMPs. AMPs have potential applications as antimicrobial
agents in food, agriculture, environment, animal husbandry and pharmaceutical in-
dustries. In this review, we have provided an overview of the structure, classification
and mechanism of action of AMPs, as well as discussed opportunities for their cur-
rent and potential applications.
KEYWORDS
antibacterial, antimicrobial peptides, antiviral, applications of AMPs, mechanism of action, origins
of AMPs
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AMPS: A PROMISING CLASS OF ANTIMICROBIAL COMPOUNDS
low risk of resistance development and even they can
inhibit antibiotic- resistant microorganisms (Hancock
& Sahl, 2006; Mahlapuu et al., 2020). All these advan-
tages make AMPs ideal candidates for pharmacological
applications.
AMPs have been reported to be effective for micro-
organisms with resistance to conventional antibiotics
(Miyoshi et al., 2016). It has been reported that persul-
catusin, an AMP, which is isolated from the tick (Ixodes
persulcatus), has an antimicrobial effect on methicillin-
resistant Staphylococcus aureus (MRSA) and vancomycin-
resistant S. aureus (VRSA; Miyoshi et al., 2017).
The synergistic effect of AMPs with antibiotics or
other AMPs can allow a more powerful inhibition (Döler
et al., 2006; Haney et al., 2009). For example, magainin
2 (MAG2) and PGLa from the skin of Xenopus laevis
frogs are the most studied AMPs that show synergis-
tic modes of action against bacterial strains by forming
transmembrane pores (Tremouilhac et al., 2006; Zerweck
et al., 2017). Similarly, combinations of jelleins and tem-
porins have a synergistic effect against S. aureus A170 and
Listeria monocytogenes (Romanelli et al., 2011). Yu et al.
(2016) showed that various binary and triple combina-
tions of six different AMPs (cecropin A, LL 19- 27, mel-
ittin, pexiganan, indolicidin and apidaecin) have strong
synergistic activity against Escherichia coli. In addition,
it was demonstrated that the membrane lytic AMPs (e.g.
protegrin 1, hBD- 3) and intracellularly active antibiotics
(e.g. gentamicin, rifampcin) showed synergistic effects
against MRSA, Micrococcus luteus, Acinetobacter bauman-
nii, Klebsiella pneumonia, Pseudomonas aeruginosa and E.
coli, though they rarely exhibited synergistically cytotoxic
effects on normal eukaryotic cells (Zharkova et al., 2019).
Combinations of AMPs with antibiotics can be proposed
as an effective strategy for the elimination of multidrug
resistant bacterial strains and decreasing antibiotic doses
in monotherapy.
Due to the increase in the number of AMPs discov-
ered naturally or designed synthetically, the need for the
creation of databases containing structure, activity, se-
quence, etc., information for AMPs has emerged. Among
them, the ‘antimicrobial activity and structure of peptides
(DBAASP) database’ contains information about more
than 2000 ribosomal, 80 non- ribosomal and 5700 syn-
thetic peptides; and includes their chemical structures and
activities against more than 4200specific target microor-
ganisms (MIC, IC50, etc.; Pirtskhalava et al., 2015). In ad-
dition to efforts for exploring new AMPs, a large number
of studies focusing on their structure, action mechanisms
and proposed production methods were performed in the
last years. This paper reviews the current and recent find-
ings regarding the mentioned studies above and presents
a detailed evaluation of known and proposed applications
of AMPs different from previous works.
STRUCTURAL CLASSIFICATION OF
AMPs
The structural organization/arrangement of AMPs is cru-
cial to understand their interaction mechanisms with the
biological targets. Many experimental methodologies,
including magnetic resonance (NMR), x- ray crystallog-
raphy, atomic force microscopy (AFM) and cryo- electron
microscopy (cryo- EM) have been integrated with compu-
tational approaches, such as molecular modelling, dock-
ing and dynamics to deeply investigate the structures and
biological functions of AMPs (Cardoso et al., 2018).
FIGURE Examples for three-
dimensional conformations of
antimicrobial peptides (https://www.
rscb.org)
α - helical
(Human LL-37, PDB ID 2K6O)
β - sheet
(Human defensin, PDB ID 6MJV)
Linear
(Bovinc indolicidin, PDB ID 5ZVF)
Mixed (Protegrin-1, PDB ID 1N5H)
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ERDEM BÜYÜKKIRAZ AND KESMEN
It is possible to classify AMPs according to a variety of
properties but the classification based on their secondary
structure is the most common. The AMP structures are gen-
erally classified into α- helical, β- sheet, mixed (α- helical/β-
sheet) and cyclic structures (Figure 1). The α- helix peptides
are the most studied AMP group. The magainin, from the
skin of the African clawed frog X. laevis, melittin found
in the venom of the honey bee Apis mellifera, and LL- 37-
derived human cathelicidin are the well- known peptides,
which present an amphiphilic α- helix secondary structure
in membrane mimetic environments (Nguyen et al., 2011;
Vandamme et al., 2012; Yang et al., 2001; Zasloff, 1987).
In this structure, the distance between the two adjacent
amino acids is about 0.15nm and the angle between them
is approximately 100° (Bahar & Ren, 2013). The presence
of the α- helix motifs (helicity) is a key factor that promotes
interactions of peptides with target membranes and al-
lows membrane disruption. When the a- helical structure
disrupts via amino acid substitutions, antibacterial activ-
ity significantly decreases (Tossi et al., 1994). The facially
amphiphilic conformation of α- helix structure, in which
cationic and hydrophobic domains are arranged on oppo-
site faces of the helix facilitates the interaction between
AMPs and membranes. The electrostatic and hydropho-
bic interactions that cause the binding and insertion of
peptides into biological membranes, respectively, are gov-
erned by these spatially segregated domains of the helix
(Wiradharma et al., 2013). While the helical structure of
AMPs significantly affects the antimicrobial potency it
is also associated with haemolytic activity and toxicity to
mammalian cells (Chen et al., 2005; Zhu et al., 2015). The
strategies based on substitutions of some - amino acids
with their - isomers to obtain stereoselectivity (Oren &
Shai, 1997) or insertion of Lys residue into the nonpolar
face of helical - peptides (Chen et al., 2006) proposed to
reduce haemolytic activity while maintaining antimicro-
bial activity. More recently, Mant et al. (2019) significantly
eliminated haemolytic activity with the substitution of
the two unusual amino acid residues, diaminobutyric acid
and diaminopropionic acid on the polar face of de novo
designed amphipathic α- helical peptides.
The second group of antimicrobial peptides exhibits β-
sheet conformation that consists of at least a pair of two
β- strands, binding with disulphide bonds. The presence
of disulphide bridges are required for the stabilization of
the structure and fulfil the biological function of peptides.
The salt bridges and head- to- tail cyclization are additional
factors that support the overall stability of the secondary
structure of the peptides. Because the β- sheet AMPs pos-
sess a more stable structure, they do not undergo essential
conformational changes upon interaction with phospho-
lipid membranes (Kumar et al., 2018). The β- sheet pep-
tides usually exhibit an amphipathic character conferred
with β- strands spatially segregated as polar and non- polar
domains (Lee et al., 2016). The β- sheet AMPs include
β- hairpin peptides and cyclic α- , β- and θ- defensins. β-
Hairpin antimicrobial peptides are characterized with
antiparallel β- sheets forming a hairpin shape that is sta-
bilized by interstrand disulphide bridges (Edwards et al.,
2016). Protegrins (PG1– PG5) are antibacterial peptides
isolated from porcine leukocytes. A stepwise pore forma-
tion model, starting with antiparallel dimerization in a
membrane environment, followed by oligomer formation
and then assembling of oligomers into an octameric pore
structure that acts as an uncontrolled ion transport chan-
nel in the biological membranes, was proposed to explain
the antimicrobial mode of action of protegrins (Usachev
et al., 2017). The tachyplesin- 1, polyphemusin- 1, gome-
sin, arenicin- 3 are other important AMPs that adopt a β-
hairpin structure.
Defensins are one of the well- described groups of AMPs
with a broad spectrum of antimicrobial activity against
bacteria, fungi and viruses. α- Defensins are mainly pres-
ent in neutrophils while β- defensins are largely secreted
in epithelial cells in various tissues (Dong et al., 2016).
Defensins contain three to six disulphide bridges and the
position intramolecular disulphide linkages determine
the class of the defensin. The disulphide- bridge linkages
that stabilized the triple- stranded β- sheet structure are
found in the positions Cys1– Cys6, Cys2– Cys4 and Cys3–
Cys5 for α- defensins and C1– C5, C2– C4 and C3- C6 for
β- defensins. The third class of defensins is the θ- defensins,
which were first isolated in rhesus macaque leukocytes.
The structure of θ- defensins is characterized by the cyclic
cysteine ladder confirmation containing a cyclic peptide
backbone cross- connected by three parallel disulphides
(Conibear et al., 2012). The cyclic cysteine ladder confor-
mation probably supports the antimicrobial activity of
θ- defensins by maintaining the structure and stability of
the cyclic backbone (Conibear et al., 2013). In addition,
the highly stabile, cyclic peptides have a large surface area
and restricted conformational flexibility, which improves
binding ability and selectivity (Falanga et al., 2017). It was
indicated that the disulphide bridges and circularity in
human θ- defensin- 1 (retrocyclin- 1) increased the receptor
binding activity and inhibited entry of HIV- 1 (Wang et al.,
2003).
A group of antimicrobial polypeptides adopts an
α- helix/β- sheet mixed structure that stabilizes three or four
disulphide bridges. This cysteine- stabilized α/β (CSαβ)
structural motif, which is composed of a single α- helix and
one β- sheet of two or three anti- parallel strands, was first
recognized in antibacterial insect defensins and scorpion
neurotoxins (Bontems et al., 1991; Zhu et al., 2005). CSαβ-
containing defensins are commonly present in plants and
insects and they have mainly shown antimicrobial activity
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AMPS: A PROMISING CLASS OF ANTIMICROBIAL COMPOUNDS
against fungi and bacteria, respectively (de Oliveira Dias &
Franco, 2015). In an amphipathic structure, the positively
charged residues are usually located in the helix while
the β- sheet of the motif consists of hydrophobic amino
acid residues (Yang, 2012). These amphipathic structures
make possible the binding and disruption of bacterial cy-
toplasmic membranes of plectasin, which is a peptide an-
tibiotic containing CSαβ motif from a saprophytic fungus
Pseudoplectania nigrella (Schneider et al., 2010). Plectasin
contains a conserved CSαβ motif sequenced as C……
CXXXC……GXC……CXC (X, any amino acid), and it is po-
tently active against drug- resistant Gram- positive bacteria
especially streptococci (Zhu, 2008).
The majority of AMPs are an unstructured form in
aqueous solutions but they undergo conformational
change and adopt a well- defined conformation depending
on the environmental conditions. For example, a cationic,
amphipathic, model peptide, GL13K is in the disordered
state in water, exhibits an α- helical structure in the pres-
ence of zwitterionic model membranes (DOPC) and tran-
sits to predominantly β- sheet conformation in anionic
membranes (DOPG; Harmouche et al., 2017).
NMR spectroscopy is a highly reliable approach for
the determination of the structure of peptides in aqueous
solution or membrane mimetic environments. Deuterated
trifluoroethanol (TFE)/water mixture has been commonly
used in solution NMR as a membrane- mimetic solvent for
determining the solution structure of peptides. However,
it has been found that deuterated detergent micelles better
simulate biological membrane environments than aque-
ous TFE. Negatively charged sodium dodecylsulphate
(SDS) molecules represent the bacterial cell membranes
while zwitterionic dodecylphosphocholine (DPC) mole-
cules mimic the eukaryotic cell membranes (Haney et al.,
2009).
NMR spectroscopy has been employed to investigate
the structure of the magainin, transiting from random coil
structure in an aqueous environment to α- helix in a vari-
ety of model membrane environments. Experimental data
based on solution NMR analysis showed that 23- residue
magainin- 2 formed α- helical between residues 2 and
22 in DPC and residues 3 and 22 in TFE/water solution
(Gesell et al., 1997). Similarly, solution NMR studies have
revealed that other amphibian antimicrobial peptide fam-
ilies such as caerin, aurein, dermaseptin and temporin
exhibit amphipathic α- helical structures in the presence
of membrane- mimetic environments or organic solvent
mixtures (Haney et al., 2009). Human cathelicidin (LL-
37) displays a salt- dependent antiparallel dimer structure,
including two amphipathic helices stabilized by back-
bone H- bonds and salt bridges (Giangaspero et al., 2001;
Zelezetsky & Tossi, 2006). Recently, Sancho- Vaello et al.
(2017) studied the atomic structure of LL- 37 in solution
and determined the presence of in vivo lipid- binding sites
between dimer interface inducing supramolecular fibre-
like oligomerization that probably represent the active
form of the peptide interacted with membranes of bac-
teria. Circular dichroism (CD) studies indicated that ce-
cropins mainly form the α- helix structure in the presence
of various membrane- mimetic environments (Sato & Feix,
2006).
ACTION MECHANISMS OF AMPs
AMPs exert their antimicrobial effects mainly through two
different mechanisms. The membrane- targeting AMPs
impair the structural integrity of the cell membrane while
the AMPs that use non- membrane targeting mechanisms
mainly inhibit the synthesis of nucleic acids, essential en-
zymes and other functional proteins (Figure 2).
Membrane active mechanisms
The membrane- active peptides can interact with micro-
bial cell surfaces via receptor- mediated or non- receptor-
mediated interactions. The first defined receptor- mediated
AMP is nisin, a bacteriocin that specifically binds to lipid
II in the initial step of the mechanism of action. This in-
teraction blocks peptidoglycan synthesis and leads to
pore formation that results in membrane permeabiliza-
tion, at even nanomolar concentrations. The most known
AMPs establish initial interaction with general targets on
a cell surface without the need for any specific receptor.
Physicochemical properties of AMPs, such as net charge,
hydrophobicity, amphipathicity, membrane curvature
and the self- aggregation tendency, have essential roles
in the administration of peptidemembrane interac-
tions resulting in disruption of the membrane integrity
(Pirtskhalava et al., 2020). The peptide– membrane inter-
actions occur by the collective effects of many of the phys-
icochemical parameters of AMPs. Therefore, it is possible
to predict the antimicrobial activity of AMPs based on the
structure- activity relationship and to design certain types
of peptides with specific properties (Kumar et al., 2018).
The mechanism of action of membrane- active AMPs is
explained mainly with cationic and hydrophobic interac-
tions. Especially, electrostatic attraction is the major driv-
ing force in the initial binding of the positively charged
residues of AMPs to the negatively charged bacterial cell
surface (Bahar & Ren, 2013; Kumar et al., 2018). The bac-
terial cytoplasmic membranes are characterized by the
high content of anionic lipids, including phospholipids
phosphatidylglycerol (PG), cardiolipin and phosphati-
dylserine, which is highly attractive for cationic AMPs,
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ERDEM BÜYÜKKIRAZ AND KESMEN
while animal membranes possess zwitterionic phospho-
lipids, such as phosphatidylcholine (PC) and sphingo-
myelin. Furthermore, teichoic acid, lipoteichoic acid and
lipopolysaccharides (LPS) are the other negatively charged
bacterial cell surface components considered as potential
targets for AMPs. Therefore, electrostatic interactions be-
tween AMPs and mammalian cell membranes are rela-
tively weak when compared to the interactions, occurring
between AMPs and bacterial membranes. Additionally,
mammalian cell membranes contain cholesterol, which
enhances membrane stability and blocks the insertion of
AMPs (Gaspar et al., 2013).
Hydrophobicity is the main feature of peptides, gov-
erning the interactions of hydrophobic residues with the
fatty acyl chains of membrane lipids and thus the inser-
tion and partition of transmembrane segments of the pep-
tides into the hydrophobic core of the bilayer (Pirtskhalava
et al., 2013). The hydrophobicity reflects the percentage of
hydrophobic residues within a peptide sequence. AMPs
achieve high antimicrobial activity at threshold hydropho-
bicity levels. In general, moderately hydrophobic peptides
have optimal activity while highly hydrophobic peptides
exhibit strong haemolytic activity and decreased antimi-
crobial activity (Chen et al., 2007; Teixeira et al., 2012).
Amphipathicity, describing the relative quantity of hy-
drophilic and hydrophobic residues located in the oppos-
ing face of peptides, contribute to the binding affinity of
α- helix AMPs to membranes. The hydrophobic residues
of amphipathic AMPs bind to a lipid bilayer while their
hydrophilic residues interact with phospholipid groups
(Bahar & Ren, 2013; Kumar et al., 2018; Li et al., 2012).
Membrane topography is an important parameter to
describe the membrane adsorption properties of the pep-
tides. Chemically distinct lipid components of biological
membranes cause spontaneous curvatures in the mem-
brane. The orientation of peptides closely related to the
lipid composition constituting membrane curvatures. The
peptides generally prefer to stay on a surface- bound state
in the membranes with negative spontaneous curvature
while they tend to embed in membranes with positive
spontaneous curvature. Additionally, the cationic peptides
have an increased electrostatic affinity for the domains of
FIGURE Action mechanism of AMPs
Unfold AMPs
Interaction with bacterial
membran of AMPs
Membran Disruption
Intracellular Targets
Carpet model
Toroidal-pore modelBarrel-stave model
Inhibition of protein synthcsis
Inhibition of DNA
and RNA synthesis
Inhibition of protein folding
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AMPS: A PROMISING CLASS OF ANTIMICROBIAL COMPOUNDS
the bacterial membrane where the accumulation of an-
ionic lipids causes negative charge abundance (Strandberg
et al., 2012). Indeed, under most conditions, membrane
curvature and lipid composition have cumulative effects
on the membrane adsorption of proteins through hydro-
phobic interactions (Vanni et al., 2014).
As the concentration of AMPs binding to the mem-
brane increases, they create peptide– peptide or lipid–
peptide complexes. Upon the accumulation of AMPs in
the membrane reaches critical aggregation concentration,
AMPs penetrate into the hydrophobic core of the bilayer
and form transmembrane pores in the cytoplasmic mem-
brane (Figure 2; Sato & Feix, 2006).
I. In the barrel- stave model, AMP molecules adsorb on
the membrane surface by the interaction of the hydro-
philic regions of peptides and self- assemble. When the
laterally accumulated peptide monomers reach a cer-
tain density on the membrane, the peptide bulks per-
pendicularly rotate to the plasma membrane. Finally,
the peptide bulks are located along the hydrophobic
region of the bilayer and construct a channel with the
hydrophilic surface directed inwards (López- Meza et
al., 2011).
II. According to the action mechanism of the toroidal
model, peptides are inserted perpendicularly in the
bilayer, similar to the barrel- stave model but form a
peptide– lipid complex instead of peptide– peptide in-
teractions. This conformation of peptides promotes a
local membrane curvature surrounded partly by pep-
tides and partly by phospholipid head groups, result-
ing in the formation of a ‘toroidal pore’ (Hazam et al.,
2018).
III. In the carpet model, antimicrobial peptides are bound
parallel to the membrane surface, thanks to an interac-
tion between the positively charged cationic peptides
and negatively charged polar phospholipid heads.
After accumulation, the peptides reach a critical con-
centration and then they reorient towards the inside
of the membranes and form micelles with a hydropho-
bic core, causing membrane disintegration (Hazam et
al., 2018).
Non- membrane active mechanisms
Although bactericidal effects of AMPs were initially de-
scribed by membrane- active mechanisms, lately, it has
been understood that many AMPs target essential cell
components and cellular functions resulting in bacterial
death. These AMPs first translocate into the cell mem-
brane without perturbing it and then prevent critical cel-
lular processes by interacting with intracellular targets.
To date, many mechanisms have been described, such as
the inhibition of protein and nucleic acid synthesis and
degradation of enzyme and protein (Brogden, 2005). The
proline- rich antimicrobial peptides (PrAMPs) are peptides
characterized by a generally high content of proline and ar-
ginine residues, which mostly display intracellular activity
by inhibiting bacterial protein synthesis. Studies showed
that PrAMPs, bactenecin 7 (Bac7) and Tur1A from bovine
and bottlenose dolphin (Tursiops truncatus), respectively
display an inhibitor effect by interacting with the ribosome
and inhibit translation by blocking the transition from the
initiation to the elongation phase (Gagnon et al., 2016;
Mardirossian et al., 2018). In another study, it was shown
that Api137, a derivative of the insect- produced AMP api-
daecin, inhibits translation by arresting the release factor
on the ribosome (Florin et al., 2017). Several transmem-
brane AMPs display an antimicrobial effect by interact-
ing with nucleic acids (DNA and/or RNA). For example,
it has been found that buforin II, a derivative of histone
obtained from frogs, passes across the bacterial membrane
and binds to the DNA and RNA of E. coli (Park et al.,
1998). The cell wall is essential for bacterial viability as it
is the main protective barrier against osmotic lysis. Several
AMPs such as copsin, a defensin from Coprinopsis cinerea,
plectasin a fungal- originated peptide and a bacteriocin
nisin inhibit the bacterial cell wall biosynthesis by binding
to the precursor lipid II, which is an essential component
in peptidoglycan synthesis (Essig et al., 2014; Hsu et al.,
2004; Schneider et al., 2010). Chaperone proteins, which
drive the proper folding and assembly of newly synthesized
proteins are other targets of AMPs showing intracellular
activity. A number of AMPs have been demonstrated to
block the important components in E. coli chaperone path-
ways. Otvos et al. (2000) proved that the insect- originated
PrAMPs, pyrrhocoricin, apidaecin and drosocin, block
the protein- folding pathway by binding specifically to the
DnaK, a 70- kDa heat shock protein, and non- specifically to
the GroEL, which is a 60- kDa bacterial chaperonin.
Approximately 80% of chronic infections in the human
are associated with microbial biofilm formation (Jamal
et al., 2018). Pathogenic biofilms comprise microbial cells
covered by a self- produced extracellular polymeric ma-
trix and are protected against conventional antimicrobial
agents (Flemming et al., 2016). In recent years, the anti-
biofilm effects of AMPs have been investigated and the
proficiency of a group of AMPs as antibiofilm agents was
demonstrated for the prevention of biofilm- related infec-
tions (Di Luca et al., 2014; Pletzer et al., 2016; Pompilio
et al., 2012). Batoni et al. (2016) suggested two modes of
action, namely classical and non- classical mechanisms,
to explain the antibiofilm activity of AMPs. The classical
mode of action is based mainly on the prevention of bio-
film formation by known bactericidal effects on planktonic
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ERDEM BÜYÜKKIRAZ AND KESMEN
bacteria (Gonzalez Moreno et al., 2017). The non- classical
mechanism is associated with an AMP action of target-
ing the essential attributes of the biofilm mode of life.
According to the non- classical model, AMPs may inhibit
cell– cell interaction by binding the bacterial surface, pre-
vent bacterial adhesion by attaching to the biomaterial
surface, interfere with cell communication signals, or
cause downregulation of the genes essential for biofilm
formation (Batoni et al., 2016; Brackman & Coenye, 2015;
de la Fuente- Nunez et al., 2012; Pletzer et al., 2016).
ORIGINS OF AMPs
AMPs from natural sources
AMPs from many species, including amphibians, insects,
mammals and fish, account for 75.65% of total AMPs,
while the remaining originate from mostly plants and bac-
teria and represent 13.5% and 8.53% of total AMPs, respec-
tively (Hazam et al., 2018).
AMPs from bacteria
Bacterial AMPs are often called bacteriocins. Although
their mechanism of action and other characteristics are
similar to those of eukaryotic AMPs, there are many dif-
ferences between them. Bacteriocins are effective at lower
concentrations than that of eukaryotic AMPs. In addition,
bacteriocins have limited effect on a few species or genera,
whereas eukaryotic AMPs can target a greater variety of
bacterial groups (Nissen- Meyer & Nes, 1997).
Bacteriocins are classified depending on size, origin,
structure and mechanisms of action. The bacteriocins ob-
tained from Gram- negative bacteria such as E. coli and/
or other enterobacteria are grouped as small peptide-
structured microcins and/or larger protein- structured
colisins (Duquesne et al., 2007). Bacteriocins produced by
Gram- positive bacteria are divided into two main groups:
lantibiotics (Class I) containing thioether- based ring
structures called lanthionine or β- methyllanthionine and
non- lantibiotics (Class II) containing unmodified antimi-
crobial peptides (Hassan et al., 2012).
Actinomycetes are an important microbial group that are
well adapted to the soil ecosystem, and they are rich sources
of peptide antibiotics (Kalyani & Rajina, 2017). In addition
to the well- known natural antibiotics such as vancomycin
and daptomycin produced by different actinomycetes spe-
cies, pargamicins B, C and D produced by Amycolatopsis
sp. ML1- hF4 (Hashizume et al., 2017), ohmyungsamycins
A and B isolated from Streptomyces sp. (Um et al., 2013)
and a lipopeptide arylomycin A6 from Streptomyces parvus
HCCB10043 (Rao et al., 2013) are novel AMPs that are ob-
tained from soil- derived actinomycetes strains.
AMPs from marine sources
The marine environment is known to be one of the rich-
est sources of antimicrobial peptides. Oceans cover just
over 70% of the Earth and are tremendous sources for the
discovery of potential AMPs (Charlet et al., 1996; Cheung
et al., 2015). Unlike the terrestrial environment, usually,
the marine environment is characterized by low tempera-
tures, high pressure, absolute darkness and high salinity
(Lauro & Bartlett, 2008). Therefore, it has been stated that
marine AMPs are structurally different from terrestrial
AMPs and are more adaptive to stringent environmental
conditions such as high salinity (Falanga et al., 2016).
Marine AMPs are isolated from microorganisms and
marine organisms. Usually, the marine AMPs are classi-
fied into four basic categories, depending on their struc-
tural and biochemical properties, without consideration
of their mechanism of action. According to this classifi-
cation, even if some peptides are in the same structural
class, their mode of action can vary considerably. Linear
α- helical AMPs (I) have hydrophobic and hydrophilic re-
gions in a linear and short- chain structure that acquire a
helical conformation after interaction with the membrane.
Clavanins, hedistin, piscidin, myxinidin, pleurocidin and
styelins are marine AMPs included in this group (Lehrer
et al., 2001; Pundir et al., 2014). Proline- and arginine- rich
callinectin (Khoo et al., 1999; Noga et al., 2011), histidine-
rich chrysophsin (Iijima et al., 2003; Mason et al., 2007),
and proline- and glycine- rich collagencin (Ennaas et al.,
2016) are linear or helical peptides with an abundance of
one amino acid (II). The third group is peptides forming a
hairpin- like β- sheet or α- helical/β- sheet mixed structures
stabilized by intramolecular disulphide bonding (III). The
most well- known example of this group is defensins, char-
acterized by multiple disulphide bonds, which provide
further stability and compactness in high salt concentra-
tions (Scudiero et al., 2010, 2013). While cyclic peptides
(IV) are isolated from the marine ecosystem in large
amounts, they generally show antimycotic activity and
their antibacterial activities have not been investigated in
detail (Falanga et al., 2016). Discodermin A, isolated from
the sea sponge, is the most well- known example of cyclic
marine AMPs (Matsunaga et al., 1985).
AMPs from plants
Plant- derived AMPs are peptides that exhibit strong and
broad- spectrum antimicrobial activity. The first reported
8
|
AMPS: A PROMISING CLASS OF ANTIMICROBIAL COMPOUNDS
plant AMP was purothionin from wheat flour (Triticum
aestivum; De Caleya et al., 1972). Most plant AMPs are
naturally basic with a molecular weight ranging from 2 to
10kDa and contain 4– 12 cysteine residues that improve
structural and thermodynamic stability (García Olmedo
et al., 2001). Generally, plant AMPs are classified accord-
ing to peptide chain length as well as the number and lo-
cation of cysteines that form disulphide bonds (de Souza
Cândido et al., 2011; Marcus et al., 1997). Numerous
plant- derived AMP groups, including defensins, snakins,
puroindolines, glycine- rich proteins, cyclotides, hevein-
type proteins, thionins, knottins and lipid transfer pro-
teins have been purified, identified and characterized
(Nawrot et al., 2014; Stotz et al., 2013; Tang et al., 2018).
These AMPs were isolated from various plant organs such
as stems, roots, seeds, flowers and leaves (Montesinos,
2007). In addition to the strong microbiocidal activity
of plant AMPs against viruses, bacteria, fungi, parasites
and protozoa, they also have anti- insect activity against
oomycetes and herbivorous pests, and anticancer activity
against some cancer cells (Allen et al., 2008; Koike et al.,
2002; Kong et al., 2004; Nawrot et al., 2014).
AMPs originated from insects
Insect antimicrobial peptides play an important role in the
humoral immune system. Insect AMPs are synthesized in
an insect's body fat and stored in haemolymph (Brown
et al., 2009; Bulet & Stocklin, 2005). More than 200 AMPs
have been identified from insects to date. These peptides
are classified under five major groups: cecropins, insect
defensins, glycine- rich peptides, proline- rich peptides and
lysozymes (Hwang et al., 2009).
Synthetic AMPs
The AMPs extracted from natural sources possess a num-
ber of problems including low stability, salt tolerance and
high toxicity that hurdle their widespread therapeutic use.
Many studies associated with the structure- activity relation-
ship of AMPs have shown that the antimicrobial activity of
peptides can be affected by changes in the structural and
physicochemical parameters (e.g. net charge, secondary
structure, hydrophobicity and amphipathicity; Cytryńska
& Zdybicka- Barabas, 2015; Huang et al., 2010). The stud-
ies investigating the structure– activity relationship (SAR) of
AMPs proved the relationship between the physicochemical
and structural properties and biological activities of natural
and de novo designed synthetic peptides. This made it pos-
sible to design peptides with broad- spectrum activity and
good stability (Porto et al., 2012; Zelezetsky & Tossi, 2006).
Several methods have been developed to design new
synthetic antimicrobial peptides by modifying the se-
quences of the naturally found antimicrobial peptides
from various organisms. It was demonstrated that small
changes in amino acid composition can lead to changes
in all conformational and physicochemical properties
of a peptide. The modifications on the template peptide
were usually performed via truncation, amino acid sub-
stitution, hybridization and/or cyclization. Obtaining
short peptides by truncating the AMP sequence provides
a cost- reduction advantage in the large- scale production
of synthetic AMPs. Cyclization of AMPs leads to higher
membrane permeability compared to linear peptides.
Hybridization is another effective strategy in synthetic
peptide design (Cardoso et al., 2021; Ong et al., 2014).
The hybrid peptides produced by combining frag-
ments cut from naturally occurring AMP sequences
allow the exploits of the different desirable properties
of template peptides. For instance, the combination of
AMPs that have low toxicity and activity, with AMPs that
exhibit high activity but relatively higher toxicity enables
the development of new chimeric AMPs with high anti-
microbial activity and low toxicity (Ong et al., 2014). De
novo AMP design makes it possible to generate peptides
with limited similarity to natural AMPs in amino acid
frequency and location. In this context, an AMP rational
design algorithm called Joker has been developed to per-
form modifications based on the introduction of antimi-
crobial motifs into the known AMP sequence (Porto et al.,
2018). These AMPs show modular character. Therefore, it
has been suggested that if a new antimicrobial motif is
added to an AMP sequence, the antimicrobial effect of
this AMP will be strengthened. Studies have shown that
amino acid residues, which are frequently encountered
in AMP databases, can be used to design peptides. For
example; KL- 12 was designed by using KR- 12 which is
the smallest antibacterial peptide derived from human
LL- 37 by turning all hydrophobic residues to leucines and
all charged and hydrophilic residues to lysine. Another
approach based on combining ‘database- derived peptide
motifs’, comprising of frequently used residues. For in-
stance; a new peptide, GLK- 19 was designed using motifs
consisting only of glycine (Gly), leucine (Leu) and lysine
(Lys) residues and found to be more active against E. coli
than human LL- 37 (Wang, Li, et al., 2009). A number
of computational approaches such as machine learning
methods, linguistic model, motif addition methods and
genetic algorithms were used to design AMPs. These
methodologies combine important information about
biochemical parameters and bioactivities of AMP se-
quences (Boone et al., 2021; Porto et al., 2012). Thus, it is
possible to predict the antibacterial potential of a candi-
date sequence prior to synthesis.
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9
ERDEM BÜYÜKKIRAZ AND KESMEN
PRODUCTION OF AMP’s
Extraction of AMPs from natural sources
AMPs are obtained from natural living forms such as
plants, frogs, insects, fungi, bacteria and other organisms
by applying a series of steps of an extraction and purifi-
cation process. Although AMPs are generally isolated
directly from raw materials by following basic extrac-
tion procedures, in some cases the further purification
of AMPs from crude extracts is performed by sophisti-
cated techniques (Moreira et al., 2011; Tang et al., 2018).
Odintsova et al. (2009) suggested an efficient method to
purify and characterize potential new AMPs from plant
materials including amino acid sequencing and a similar-
ity search in databases.
AMPs produced by chemical synthesis
The chemical synthesis of AMPs is performed by solid-
phase peptide synthesis (SPPS; Bray, 2003). The growing
chain (peptide or oligomer) is attached to a solid support
such as a resin or bead and remains adhered to this sup-
port during synthesis. To minimize racemization, the
peptide synthesis starts from the C- terminus. The pep-
tide growth takes place by applying a selective coupling
based on the ‘Fmoc strategy’ between the carboxylic acid
group of the added amino acid and the amino- terminal
group of the amino acid attached to the solid phase. High
concentrations of reagents are used during the synthesis
and excess reagents can be easily removed by the washing
and filtering steps after each binding step. The disadvan-
tages of solid- phase peptide synthesis are the cost of the
solid support, the limited number of the ‘linker’ groups on
the surface of the bead and the use of toxic reagents that
lead to adverse environmental effects. Although, peptides
shorter than 30 amino acids can be synthesized using this
method, longer peptides only have a 55% correct sequence
rate of the target peptide (Chan & White, 2000; Fields &
Noble, 1990).
AMPs produced from genetically
modified organisms
Traditional production methods of AMPs are associated
with some limitations. For example, the purification
of AMPs from natural sources such as bacteria, plants,
frogs, insects, or fungi is expensive and time- consuming
(Ingham & Moore, 2007). Moreover, production of AMPs
with standard activity and high purity is generally dif-
ficult and a specific extraction method is required for
the purification of AMPs from each source (Parachin
et al., 2012). However, in the chemical synthesis of AMPs,
which is another conventional method, the cost is quite
high, and therefore, peptide synthesis is suitable for only
small- scale production, such as laboratory applications.
Therefore, the recombinant production of AMPs based
on the expression of AMP genes from natural sources in
host organisms has become a more attractive method in
recent years. Furthermore, in recombinant production, it
may be possible to make modifications in the peptide se-
quence or to produce fully synthetic analogous peptides
for specific purposes such as increasing peptide stability
or/and production of hybrid AMPs with high antimicro-
bial activity (Bahar & Ren, 2013; Piers et al., 1993; Ramos
et al., 2013; Wade et al., 2012).
Many bacterial host cells have been used for the ex-
pression of AMPs. However, E. coli is the most preferred
recombinant bioreactor because of its rapid growth and
well- known genetic, physiological and biochemical fea-
tures (Ingham & Moore, 2007). In the expression of AMPs
in bacterial hosts, combining the antibacterial peptide
with a carrier protein reduces the lethal effect of the
peptide on the host organism and provides resistance to
proteolytic degradation (Vassilevski et al., 2008). Several
recombinant AMPs such as dermsidin (DCD), ABP- CM4
peptide, LfcinB- W10 (a derivative bovine lactoferricin),
protegrin- 1 (PG- 1), cathelicidin LL- 37 and some beta-
defensins have been produced by fusion protein strategy
in E. coli. In addition, hybrid AMPs with different prop-
erties have been designed and expressed by the combi-
nation of multiple AMP genes to increase antimicrobial
activities of heterologous products and obtain a high yield
(Rodriguez- Cabello et al., 2012).
Pichia pastoris (Komagataella phaffii) is the most widely
used and studied yeast expression system for the produc-
tion of eukaryotic heterologous proteins (Balamurugan
et al., 2007). Successful expression of AMPs, including
cecropins (Jin et al., 2006; Wang et al., 2011), defensins
(Hsu et al., 2009), ABP- CM4 peptide (Zhang et al., 2006)
and human CAP18/LL37 AMP (Kim et al., 2009), was
performed in the P. pastoris expression system. In addi-
tion, the expression of hybrid AMPs has been successful
in P.pastoris (Jin et al., 2009). The P. pastoris expression
system was considered an ideal heterologous host because
it allowed numerous eukaryotic post- translational modifi-
cations such as glycosylation, signal sequencing process-
ing and disulphide bond formation, which are required for
cysteine- rich cationic AMPs (Cereghino & Cregg, 2000).
For example, this system was used for the expression of
HD5, a cationic peptide with six cysteine residues forming
three intramolecular disulphide bonds (Hsu et al., 2009).
Various diseases caused by viruses, bacteria or fungi
negatively affect agricultural production and cause
10
|
AMPS: A PROMISING CLASS OF ANTIMICROBIAL COMPOUNDS
economic losses. Product losses caused by phytopatho-
gens and pests have been reported to reach 30%– 40% per
year in developing countries (Flood, 2010). AMPs are con-
sidered a good candidate for the control of plant diseases
(Holaskova et al., 2015). AMPs, expressed in model plants
provided varying degrees of protection against plant
pathogens (Montesinos, 2007).
Plant bioreactors are also alternative recombinant ex-
pression systems that have been widely used to produce
pharmaceuticals and therapeutics. High yield expression
of AMPs in plant bioreactors offers an excellent option for
large- scale production of medical products due to the in-
creasing demand (da Cunha et al., 2017; Tregoning et al.,
2005). Plant bioreactors are low- cost production systems
for the synthesis of large quantities of heterologous poly-
peptides in various organs of plants since they only require
soil, water and light (Davies, 2010; Obembe et al., 2011).
Cn- AMP1, clavanin A, Cm AMP- 5 and parigidina- br1,
which have antimicrobial and insecticidal activities, were
expressed in high yields in the leaves of the tobacco plant
(Nicotiana benthamiana; Leite et al., 2018).
APPLICATIONS OF AMPs
In recent decades, antibiotic- resistant bacterial infections
are an alarmingly and increasing worldwide problem not
only in the medical industry but also in animal husbandry
and aquaculture. The urgent need for developing alter-
native agents to control microbial diseases has been the
major driving force in the development of peptide antibiot-
ics, which could become the most potent solution in cases
where current antibiotics are insufficient (Global Peptide
Antibiotics Market & Clinical Pipeline Insight, 2023).
However, AMPs are multi- functional agents that have also
several therapeutic functions such as anti- inflammatory,
immunomodulatory, endotoxin- neutralizing activities and
cytotoxic effects on cancer cells, which make them good
candidates for pharmacological practices, besides their di-
rect antimicrobial effects (Gordon et al., 2005; Kang et al.,
2017). Rapid and broad- spectrum activities, multipurposes
use opportunities and low resistance development poten-
tials of AMPs are the main factors increasing their appeal
in the biopharmaceutical industry and investment in the
peptide antibiotics market. The Global Antimicrobial
Peptides market was valued at 5million USD in 2020 and
will reach 6million USD by the end of 2027 at a compound
annual growth rate (CAGR) of 5.4% between 2022 and
2027 (Global Antimicrobial Peptides Sales Market Report,
2021). Currently, more than 60 peptides are approved by
the US Food and Drug Administration (FDA) and over
400 peptides are under clinical phase trials (Agarwal &
Gabrani, 2021).
Pharmaceutical practices
AMPs are one of the most promising antibiotic candidates
to overcome challenges regarding multidrug resistance.
They can be used alone or in combination with conven-
tional antibiotics, antivirals or other antimicrobial com-
ponents to obtain a synergistic effect (Gordon et al., 2005).
Although only a few AMPs have been approved by the
FDA up to now, there are numerous AMPs under preclini-
cal stages or clinical trials (Koo & Seo, 2019). Daptomycin
is a cyclic lipopeptide that exhibits a fast bactericidal ef-
fect against various drug- resistant Gram- positive bacteria.
It was approved by the FDA in 2003, for the treatment of
complicated skin and skin structure infections (Carpenter
& Chambers, 2004). Another peptide antibiotic, vanco-
mycin is a tricyclic glycopeptide that shows a killer effect
against Gram- positive bacteria by inhibiting the synthe-
sis of the peptidoglycan layer of the bacterial cell wall.
Vancomycin was approved by the FDA for clinical uses
of Clostridium difficile- associated diarrhoea, pseudomem-
branous colitis and S. enterocolitis, and infections (Patel
et al., 2020). Dalbavancin, oritavancin and telavancin
are semisynthetic lipoglycopeptide derivatives of vanco-
mycin, which were approved by the FDA between 2009
and 2014 for the treatment of complicated skin and skin
structure infections. Their antibacterial activity has been
improved through liposaccharide elements attached to
the peptide, which increase the binding ability with bacte-
rial cells (Bambeke, 2015). The polymyxins (colistin and
polymyxin B) are well- characterized cyclic lipopeptide
antibiotics that have been used clinically for the treatment
of multidrug Gram- negative bacterial infections since the
late 1950s. Polymyxin B and colistin possess similar action
mechanisms, attributed to their similar chemical struc-
tures and they act on Gram- negative bacteria with minor
differences. Colistin is mainly marketed as its inactive
prodrug form, colistin methanesulphonate (CMS), and is
administered intravenously or intramuscularly. However,
polymyxin B is infused parenterally in its active sulphate
form (Tran et al., 2016; Vardakas & Falagas, 2017).
Histatin is a histidine- rich cationic salivary peptide
with strong anticandidal activity. The phase I and II clin-
ical trials of PAC113, which is a derivative histatin, have
been shown to be a promising drug for the treatment
and prevention of oral candidiasis (Koo & Seo, 2019).
Omiganen pentahydrochloride (MBI- 226) is a synthetic
analogue of indolicidine, which is a cationic peptide that
originated from bovine neutrophils. In vitro activity of
MBI- 226has been demonstrated against 1437clinical bac-
terial isolates and 214 clinical yeasts (Sader et al., 2004)
and its phase III clinical trial has been completed for the
treatment of rosacea (Table 1). Human lactoferrin and
its variety of derivatives were evaluated to produce drugs
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11
ERDEM BÜYÜKKIRAZ AND KESMEN
effective against bacterial, fungal and viral infections. For
instance, human lactoferrin 1- 11 (hLF1- 11) is a derivative
with broad- spectrum antibacterial and antifungal activity,
which has been developed for intravenous treatment of
bacterial and fungal infections in immune- compromised
stem cell transplant recipients (van der Velden et al., 2009).
Novexatin (NP213) is a cyclic fungicidal peptide, which ef-
fectively penetrates the human nail, has been proposed for
the topical treatment of onychomycosis (fungal nail infec-
tion; Mercer et al., 2020).
In globalized world, epidemic and pandemic infections
caused by the emergence or re- emergence of virus strains
are a growing threat to the world population. AMPs ex-
hibit antiviral activity by virus- targeting or host- targeting
action mechanisms. The virucidal mechanism of action
describes the direct effect of AMPs against viral particles,
based on lysis of envelope or inhibition of essential viral
components. In contrast, the host- focused mechanism is
related with interfering the viral binding site in the host
cell membrane and blocking of adsorption (Boas et al.,
2019). Up to now several natural or rationally designed
AMP’s were tested against human immunodeficiency
virus (HIV), zika virus (ZIKV), respiratory syncytial virus
(RSV; He et al., 2018), hepatitis C virus (HCV; El- Bitar
et al., 2015), severe acute respiratory syndrome corona-
virus (SARS- CoV), influenza A (H5N1, H1N1; Li et al.,
2011), herpes simplex virus (HSV), hepatitis B virus (HBV;
Zeng et al., 2018), vaccinia virus (VV; Howell et al., 2004),
etc. An HIV fusion inhibitor Enfuvirtide (trade name
Fuzeon) is a synthetic 36- amino acid peptide that is FDA
approved for combination therapy of HIV- 1 infection. A
more efficient HIV fusion inhibitor peptide, sifuvirtide,
which can effectively inhibit HIV replication and exhibit
high activity against ENF- resistant HIV- 1strains, is under
phase II clinical trial (Wang, Yang, 2009; Yao et al., 2012).
Other FDA- approved peptides are boceprevir and telapri-
vir, used in the treatment of chronic hepatitis C (HCV),
genotype 1. They are selective protease inhibitors block-
ing the activity of the viral HCV nonstructural [NS] region
3/4 serine protease that is essential for viral replication
(Agarwal & Gabrani, 2021). Anti- SARS- CoV activities of
heptad repeat (HR)- based peptides were demonstrated
against coronaviruses in several studies (Outlaw et al.,
2020; Ujike et al., 2008; Xia et al., 2020; Yuan et al., 2004).
For example, EK1 is a modified form of the OC43- HR2P
peptide, which exhibited broad fusion inhibitory activ-
ity against multiple human coronaviruses (HCoVs). A
cholesterol- conjugated derivative of the EK1, EK1C4 was
tested against SARS- CoV- 2. The EK1C4 exhibited 240- fold
more potent inhibitory activity against SARS- CoV- 2spike
protein- mediated membrane fusion than the EK1 peptide
(Xia et al., 2020). In another study, Outlaw et al. (2020)
described a derivative lipopeptide from the C- terminal
heptad repeat (HRC) domain of SARS- CoV- 2 S conju-
gated with tetra- ethylene glycol- cholesterol, which inhib-
its cell- cell fusion mediated by SARS- CoV- 2 S and blocks
infection.
Since AMPs are one of the most promising antimicro-
bial drug candidates, understanding the bacterial resis-
tance mechanisms that are developed against AMPs is a
critical issue (Bechinger & Gorr, 2017). AMPs act on di-
verse bacterial cellular targets through multiple mecha-
nisms, therefore resistance development is less common
compared to conventional antibiotics (Browne et al.,
2020). However, various bacterial resistance mechanisms
have been reported acquired against AMPs. Many defence
strategies are based on modification cell surface compo-
nents since the cell membrane is the main target of at-
tack of AMPs. The changes in the charge and fluidity of
external cell structures often contribute to the resistance
by reducing the attachment and insertion of AMPs to the
bacterial cell surface (Joo et al., 2016). Proteolytic deg-
radation of the peptides is another potential resistance
mechanism and strongly depends on the peptide structure
since many secreted proteases are nonspecific for AMPs
(Pfalzgraff et al., 2018). The efflux pumps expelling the
harmful substances and capsular polysaccharides serving
as a barrier that protects the bacteria are other important
bacterial defence mechanisms that contribute to the resis-
tance against AMPs (Abdi et al., 2019). Compared to anti-
biotics, the resistance to AMPs occurs through nonspecific
and intrinsic mechanisms, and horizontal transfer of re-
sistance genes generally occurs at a lower frequency (Joo
et al., 2016). This may be considered a factor, increasing
the medical importance of AMPs and stimulating their ap-
plications as substitutes for antibiotics.
Food applications
AMPs can be used as food additives in the food industry
or they can also be included in the composition of pack-
aging materials. Nisin, an antimicrobial peptide produced
naturally by Lactococcus lactis, is a bacteriocin in the
group of lantibiotics. Nisin is the only bacteriocin licensed
in more than 50 countries. Although nisin can inhibit
Gram- positive food- borne pathogenic and spoilage bacte-
ria, it is ineffective on yeast and Gram- negative bacteria.
An iron- binding glycoprotein, lactoferrin is an effective
antimicrobial peptide founding in milk and colostrum.
Lactoferrin has been approved for use as an antimicrobial
agent in meat products in the USA (USDA- FSIS 2008 FSIS
Directive 7120.1 Amendment 15). Pepsin digested lactofer-
rin derivative lactoferricin is a more potent antimicrobial
peptide and offers a potential advantage in food preserva-
tion due to its relative heat resistance (Villalobos- Delgado
12
|
AMPS: A PROMISING CLASS OF ANTIMICROBIAL COMPOUNDS
et al., 2019). ε- Polylysine is a homopolymer of - lysine
originated by Streptomyces albulus, which has broad-
spectrum antimicrobial activity in Gram- positive and
Gram- negative bacteria, yeast, mould and viruses. It has
been approved by FDA as a food preservative in gener-
ally recognized as safe (GRAS) status (Luz et al., 2018).
Natamycin, produced by Streptomyces species, is an effec-
tive bacteriocin against almost all food- borne yeasts and
TABLE Peptide- based antimicrobial compounds in clinical trials (http://dramp.cpu- bioin for.org/)
DRAMP ID NAME Description Activity Medical use Development Stage
DRAMP18062 Histatin Using a variant of histatins, which are naturally occurring
cationic peptides in saliva
Antifungal Chronic Pseudomonas aeruginosa infections Phase I
DRAMP18061 Histatin Using a variant of histatins, which are naturally occurring
cationic peptides in saliva
Antifungal Antimicrobial- peptide- containing mouth wash for the
treatment of oral candidiasis (gingivitis and periodontal
diseases)
Phase II- III
DRAMP18068 hLF1- 11 An 11- mer peptide from the N terminus of human lactoferrin Antibacterial, Antifungal LPS- mediated diseases and fungal infections Phase I (completed)
DRAMP18178 IDR- 1 Derivative of bactenecin from bovine neutrophils Chemokine induction and
reduction of pro- inflammatory
cytokines
Prevention of infections in the immune compromised Phase I
DRAMP18080 Plectasin A fungal defensin (Pseudoplectania nigrella) Antibacterial Systemic anti- Gram positive, especially pneumococcal and
streptococcal infections
Phase I
DRAMP18166 Vasoactive intestinal peptide (VIP) A peptide hormon Antibacterial Acute respiratory distress syndrome and sepsis Phase I
DRAMP18153 Opebacan 21- amino- acid peptide derivative of bactericidal/permeability-
increasing protein
Antibacterial, Antiviral Endotoxaemia in haematopoetic, stem cell transplant,
recipients
Phase I/II
DRAMP20761 LTX- 109 A chemically synthesized, peptide- mimetic bactericidal
antimicrobial drug
Antibacterial Treatment of nasal carriers MRSA Phase I/IIa
DRAMP18164 AP- 214 Synthetic derivative from α- melanocyte- stimulating hormone Antibacterial Sepsis and post- surgical organ failure Phase II (completed)
DRAMP20760 C16G2 A synthetic AMP Antibacterial Treatment of adult and adolescent dental subjects Phase II
DRAMP18083 CZEN- 002 Synthetic 8- mer derived from α- melanocyte- stimulating
hormone
Anticandidal Vulvovaginal candidiasis Phase IIb
DRAMP18088 EA- 230 A derivative peptide from the human pregnancy hormone Anti- inflammatories; Antiseptics Sepsis Phase II
DRAMP18163 Ghrelin Endogenous host- defence peptide, synthetic construct Anti- inflammatory Airway inflammation, chronic respiratory infection and cystic
fibrosis
Phase II (completed)
DRAMP18152 IMX942 Synthetic cationic host defence peptide, derivative of IDR- 1 and
indolicidin
Antibacterial Nosocomial infections, febrile, neutropenia Phase II
DRAMP18067 MX- 594AN Indolicidin based antimicrobial peptide variant Antibacterial, Antifungal The treatment of catheter- related infections and acne Phase IIb (completed)
DRAMP18157 Novexatin (NP213) Cyclic cationic peptide derived from NovaBiotics arginine
peptide platform
Antifugal Treatment of dermatophyte fungal infections such as
onychomycosis
Phase IIb
DRAMP18161 OP- 145 Synthetic 24- mer peptide derived from LL- 37 Antibacterial Chronic bacterial middle ear infection. Phase II (completed)
DRAMP18063 P113 A 12 amino acid fragment of histatin 5 Antifungal HIV Phase II (completed)
DRAMP18081 PAC113 A 12 amino- acid antimicrobial peptide derived from histatin Antifungal Oral candidiasis Phase IIb
DRAMP28983 PL- 5 An α- helical AMP developed by ProteLight Pharmaceuticals Antibacterial Skin wound infection Phase II
DRAMP18158 PMX- 30063
(brilacidin)
Defensin structural mimetic, non- peptide, small molecule/
copolymer
Antibacterial Acute bacterial skin infections caused by Staphylococcus spp. Phase II
DRAMP18182 Sifuvirtide (SFT) Designed based on the 3D structure of the HIV- 1gp41
fusogenic core conformation
Anti- HIV HIV fusion inhibitor; AIDS Phase II
DRAMP18154 XOMA- 629 9- amino- acid peptide derivative of bactericidal/permeability-
increasing protein
Antibacterial Impetigo Phase IIA
DRAMP18070 XMP 629 A 9- amino- acid peptide derived from bactericidal/permeability-
increasing protein (BPI)
Antibacterial Acne Phase III
DRAMP18071 Mycoprex Extracted from insects Antifungal Fungal infections Phase III
DRAMP20774 Murepavadin (POL7080) A synthetic analogue of protegrin I Antibacterial Treatment of nosocomial pneumonia and ventilator-
associated bacterial pneumonia (VABP)
Phase III
DRAMP18160 Omiganan (MBI- 226) A synthetic analogue of indolicidine Antibacterial Treatment of rosacea Phase III (completed)
|
13
ERDEM BÜYÜKKIRAZ AND KESMEN
moulds, although it is not effective in bacteria or viruses.
To inhibit fungal growth natamycin is applied on the sur-
face of cheese and salami- type sausages (Elsser- Gravesen
& Elsser- Gravesen, 2014). Spheniscin is an avian- defensin
defined in king penguins (Aptenodytes patagonicus),
which preserves undigested food in their stomach for the
last part of the egg incubation period. This event gave re-
searchers a good idea that sphenicin may be used in the
TABLE Peptide- based antimicrobial compounds in clinical trials (http://dramp.cpu- bioin for.org/)
DRAMP ID NAME Description Activity Medical use Development Stage
DRAMP18062 Histatin Using a variant of histatins, which are naturally occurring
cationic peptides in saliva
Antifungal Chronic Pseudomonas aeruginosa infections Phase I
DRAMP18061 Histatin Using a variant of histatins, which are naturally occurring
cationic peptides in saliva
Antifungal Antimicrobial- peptide- containing mouth wash for the
treatment of oral candidiasis (gingivitis and periodontal
diseases)
Phase II- III
DRAMP18068 hLF1- 11 An 11- mer peptide from the N terminus of human lactoferrin Antibacterial, Antifungal LPS- mediated diseases and fungal infections Phase I (completed)
DRAMP18178 IDR- 1 Derivative of bactenecin from bovine neutrophils Chemokine induction and
reduction of pro- inflammatory
cytokines
Prevention of infections in the immune compromised Phase I
DRAMP18080 Plectasin A fungal defensin (Pseudoplectania nigrella) Antibacterial Systemic anti- Gram positive, especially pneumococcal and
streptococcal infections
Phase I
DRAMP18166 Vasoactive intestinal peptide (VIP) A peptide hormon Antibacterial Acute respiratory distress syndrome and sepsis Phase I
DRAMP18153 Opebacan 21- amino- acid peptide derivative of bactericidal/permeability-
increasing protein
Antibacterial, Antiviral Endotoxaemia in haematopoetic, stem cell transplant,
recipients
Phase I/II
DRAMP20761 LTX- 109 A chemically synthesized, peptide- mimetic bactericidal
antimicrobial drug
Antibacterial Treatment of nasal carriers MRSA Phase I/IIa
DRAMP18164 AP- 214 Synthetic derivative from α- melanocyte- stimulating hormone Antibacterial Sepsis and post- surgical organ failure Phase II (completed)
DRAMP20760 C16G2 A synthetic AMP Antibacterial Treatment of adult and adolescent dental subjects Phase II
DRAMP18083 CZEN- 002 Synthetic 8- mer derived from α- melanocyte- stimulating
hormone
Anticandidal Vulvovaginal candidiasis Phase IIb
DRAMP18088 EA- 230 A derivative peptide from the human pregnancy hormone Anti- inflammatories; Antiseptics Sepsis Phase II
DRAMP18163 Ghrelin Endogenous host- defence peptide, synthetic construct Anti- inflammatory Airway inflammation, chronic respiratory infection and cystic
fibrosis
Phase II (completed)
DRAMP18152 IMX942 Synthetic cationic host defence peptide, derivative of IDR- 1 and
indolicidin
Antibacterial Nosocomial infections, febrile, neutropenia Phase II
DRAMP18067 MX- 594AN Indolicidin based antimicrobial peptide variant Antibacterial, Antifungal The treatment of catheter- related infections and acne Phase IIb (completed)
DRAMP18157 Novexatin (NP213) Cyclic cationic peptide derived from NovaBiotics arginine
peptide platform
Antifugal Treatment of dermatophyte fungal infections such as
onychomycosis
Phase IIb
DRAMP18161 OP- 145 Synthetic 24- mer peptide derived from LL- 37 Antibacterial Chronic bacterial middle ear infection. Phase II (completed)
DRAMP18063 P113 A 12 amino acid fragment of histatin 5 Antifungal HIV Phase II (completed)
DRAMP18081 PAC113 A 12 amino- acid antimicrobial peptide derived from histatin Antifungal Oral candidiasis Phase IIb
DRAMP28983 PL- 5 An α- helical AMP developed by ProteLight Pharmaceuticals Antibacterial Skin wound infection Phase II
DRAMP18158 PMX- 30063
(brilacidin)
Defensin structural mimetic, non- peptide, small molecule/
copolymer
Antibacterial Acute bacterial skin infections caused by Staphylococcus spp. Phase II
DRAMP18182 Sifuvirtide (SFT) Designed based on the 3D structure of the HIV- 1gp41
fusogenic core conformation
Anti- HIV HIV fusion inhibitor; AIDS Phase II
DRAMP18154 XOMA- 629 9- amino- acid peptide derivative of bactericidal/permeability-
increasing protein
Antibacterial Impetigo Phase IIA
DRAMP18070 XMP 629 A 9- amino- acid peptide derived from bactericidal/permeability-
increasing protein (BPI)
Antibacterial Acne Phase III
DRAMP18071 Mycoprex Extracted from insects Antifungal Fungal infections Phase III
DRAMP20774 Murepavadin (POL7080) A synthetic analogue of protegrin I Antibacterial Treatment of nosocomial pneumonia and ventilator-
associated bacterial pneumonia (VABP)
Phase III
DRAMP18160 Omiganan (MBI- 226) A synthetic analogue of indolicidine Antibacterial Treatment of rosacea Phase III (completed)
14
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AMPS: A PROMISING CLASS OF ANTIMICROBIAL COMPOUNDS
long- term preservation of foods (Thouzeau et al., 2003).
Pediocins, other bacteriocins synthesized by Pediococcus
acidilactici and Pediococcus pentosaceus have been sug-
gested to be used for the preservation of vegetable and
meat products (Papagianni & Anastasiadou, 2009; Figure
3).
The integration of volatile or non- volatile antimicro-
bial agents with packing materials is one of the most in-
teresting issues in active packaging. In the development of
antimicrobial packaging, AMPs were coated on polymer
surfaces by adsorption or immobilization (Appendini &
Hotchkiss, 2002). Many AMPs, including cecropins, defen-
sin and magainins may be coupled to polymers alone or in
combination with antibiotics, certain organic acid and en-
zymes, such as lactoperoxidase and lysozyme (Suppakul
et al., 2003). Dermaseptin K4K20- S4, which shows anti-
microbial activity against a wide range of pathogenic mi-
croorganisms, has been incorporated into different food
coatings and showed significant inhibition effect against
mould and aerobic bacteria (Miltz et al., 2006). The incor-
poration of AMPs with food packaging material instead
of antimicrobial additives directly added to bulk food pro-
vides a significant reduction of microbial load that occurs
on the surface of foods. This application may increase
the protection efficiency by allowing only the required
amount of peptide to be released. The gradual release of
an antimicrobial from packaging material to the food sur-
face may contribute an advantage over other applications,
such as dipping and spraying. In current applications, the
activity of antimicrobial agents may rapidly reduce due
to their interaction with food components (Appendini &
Hotchkiss, 2002; Gennadios et al., 1997). In a study on
non- degradable films incorporated with antimicrobial
peptide Gramicidin A, a partial release of the peptide from
the film was demonstrated with partial inhibition of the
bacterial growth, and consequently strong antibacterial
activity was observed (Guyomard et al., 2008).
Animal husbandry applications
The emergence of antibiotic- resistant bacteria in animal
products has become a serious threat to public health and
food security because of the potential risk related to anti-
biotic resistance genes that may be transferred from bacte-
ria to humans. Antimicrobial peptides, which have strong
therapeutic effects and weak resistance developmental
ability represent one of the most favourable alternatives for
the management of crises concerning antibiotic- resistant
microbes and achieving sustainable livestock production.
FIGURE Classification of AMPs according to their different properties
|
15
ERDEM BÜYÜKKIRAZ AND KESMEN
The potential of AMPs to treat microbial infections was
evaluated for many critical diseases in livestock. It has
been reported that the dietary supplementation of broiler
chickens with nisin exerted a clearly modulating effect
on the gut microbial ecology and significantly decreased
counts of Bacteroides and Enterobacteriaceae in ileum di-
gesta (Józefiak et al., 2013).
Transgenic expression of AMPs can be an effective
strategy to overcome some important problems of animal
husbandry that directly affect both animal health and
milk yield, such as mammary gland infection (mastitis;
Donovan et al., 2005). For example, mammary gland ex-
pression of bovine lactoferricin and human lactoferrin in
transgenic goats conferred a wide spectrum of antimicro-
bial activity against several pathogens (Zhang et al., 2007,
2008).
Dietary supplementation of antibiotics was a common
practice to prevent disease outbreaks and improve feed ef-
ficiency until banned by the EU in 2006 (Hao et al., 2014).
Recently, AMPs have been proposed as an alternative to
conventional antibiotic feed additives for improving the
growth performance and health of the animals. Several
studies indicated that the addition of the AMPs to wean-
ling pig diets beneficially affects the host by improving
growth performance, health condition and immune func-
tions and reducing harmful gut microflora. For exam-
ple, antimicrobial peptide colisin E1 (Cutler et al., 2007),
cipB- lactoferricin- lactoferrampin (Tang et al., 2008), and
Cecropin AD (Wu et al., 2012) increased immune function
and reduced intestinal pathogens. In another experiment,
the positive effects on the growth performance, and coef-
ficient of total tract apparent digestibility and intestinal
morphology of weanling pigs fed a diet supplemented
with synthetic antimicrobial peptide- A3 (AMP- A3) were
observed. It was also reported that the dietary supplemen-
tation of increasing levels of the AMP- A3linearly reduced
the faecal and intestinal TAB, coliforms and Clostridium
spp. in weanling pigs (Yoon et al., 2012). In a recent study,
the antimicrobial peptide, Epinephelus lanceolatus pis-
cidin (EP) was expressed in Pichia pastoris host cell and
recombinant EP (rEP) was then used as a dietary supple-
ment for Gallus gallus domesticus. The rEP supplementa-
tion increased body weight, feed efficiency and the levels
of interleukin- 10 and interferon- γ in the supplemented
group Gallus gallus domesticus more than in the control
(Tai et al., 2020).
AMPs have been demonstrated as promising antivi-
ral agents in the fight against animal infecting viruses,
such as severe acute respiratory syndrome coronavirus
(SARS- CoV; Elnagdy & AlKhazindar, 2020), porcine ep-
idemic diarrhea virus (PEDV; Guo et al., 2018), porcine
transmissible gastroenteritis virus (TGEV; Liang at al.,
2020), infectious bronchitis virus (IBV; Sun et al., 2010)
and influenza A (Hsieh & Hartshorn, 2016). The antiviral
activity of swine intestine antimicrobial peptides (SIAMP)
was assessed against infectious bronchitis virus (IBV) in
chick embryos. The mortality caused by IBV was reduced
remarkably in the SIAMP- treated chick embryos. This re-
sult was attributed to the interaction of SIAMP with IBV,
which blocked the binding of IBV to host epithelial cells
and thus, inhibited virus replication (Sun et al., 2010). In
another study, the inhibitory effect of porcine leukocytes
originated protegrin- 1 (PG- 1) against porcine reproductive
and respiratory syndrome virus (PRRSV) was investigated
in PRRSV infected Marc- 145 cells or porcine alveolar mac-
rophages (PAMs). The PG- 1 treatment specifically blocked
the viral attachment stage, probably due to the presence
of specific virus receptor molecules in Marc- 145 cells and
thus inhibited viral replication but a similar inhibition ef-
fect was not observed in PAMs (Guo et al., 2015).
Applications in aquaculture
Fish and other aquatic products are important sources
of animal proteins and other essential nutrients needed
in the human diet. Although aquaculture is one of the
fastest- growing animal food production sectors in the
world (FAO, 2020), microbial disease outbreaks are con-
sidered the major sectoral problem that leads to signifi-
cant economic losses (Paria et al., 2018). The use of AMPs
can also eliminate detrimental microorganisms in an aq-
uaculture environment, where antibiotic usage is limited
due to increasing resistance. For instance, in earlier stud-
ies, synthetic AMP epinecidin- 1 demonstrated antimi-
crobial activity against a group of bacteria such as E. coli,
Pasturella multocida, Aeromonas sobrio, A. hydrophila,
Morganella morganii, Flavobacterium meningosepticum
and Vibrio species, including V. parahaemolyticus, V. vul-
nificus, V. alginolyticus, which are considered detrimental
to aquacultural organisms (Yin et al., 2006). Furthermore,
it was found that co- incubation of native cecropin B and
a synthetic analogue CF17 with some important fish viral
pathogens (infectious hematopoietic necrosis virus, viral
haemorrhagic septicaemia virus, snakehead rhabdovirus
and infectious pancreatic necrosis virus) decreased viral
titres up to 104- fold (Chiou et al., 2002).
A recent study by León et al. (2020) demonstrated that
the in vitro antibacterial and antiviral activity of several
synthetic peptides, such as frog caerin1.1, dicentracin
(Dic) and NK- lysin peptides (NKLPs) and sole NKLP27.
The majority of peptides exhibited strong antibacterial
activity against all tested human and fish pathogenic bac-
teria except Aeromonas salmonicida, and inhibits a wide
spectrum of fish viruses that are considered the most dev-
astating viruses for aquaculture. It was demonstrated that
16
|
AMPS: A PROMISING CLASS OF ANTIMICROBIAL COMPOUNDS
the NKL- 24, a truncated peptide derived from zebrafish
NK- lysin had a potent antibacterial effect against V. par-
ahaemolyticus via disruption of the membrane permeabi-
lization (Shan et al., 2020). Recently, antibiotic- resistant
V. parahaemolyticus was detected from aquatic farmed
products such as scallops (De Silva et al., 2019), shrimps
(Letchumanan et al., 2019) and shellfish (Lopatek et al.,
2015). Hu et al. (2019) proposed Malabar grouper pisci-
din 1 (EmPis- 1) as a safe and efficient agent for eliminat-
ing the viable but non- culturable (VBNC)- state cells of
ampicillin and kanamycin- resistant pathogenic bacteria.
They demonstrated that full- length and truncated forms
of EmPis- 1 could effectively kill the antibiotic- resistant
E. coli Top10, S. aureus and V. parahaemolyticus OS4 by
membrane disruption and cell lysis at a concentration of
less than 10μmol/L.
Plant protection applications
Every year around the world, high amounts of pesticides
are used to prevent yield losses caused by plant patho-
gens and insects. However, long- term usage of chemi-
cal pesticides is one of the most important reasons for
environmental pollution and leads to human health
problems (Naik et al., 2006). AMPs are good candidates,
which can be used against phytopathogens in various
fields of agriculture, without any side effects for the en-
vironment, humans or animals (Zasloff, 2002). In vitro,
experimental studies reported useful results to evalu-
ate the potency of many candidate peptides to be used
in plant protection. For instance, antibacterial activi-
ties of the three synthetic peptides including iseganan,
pexiganan, and the cecropin- melittin hybrid peptide
CAMEL, were demonstrated to inhibit in vitro growth of
phytopathogenic bacteria Pectobacterium carotovorum
and Pectobacterium chrysanthemi (Kamysz et al., 2005).
In several studies, the antifungal and antibacterial ac-
tivities of synthetic cecropin A- melittin hybrid peptides
were tested against important plant pathogens. Ferré
et al. (2006) synthesized short cecropin- A melittin hy-
brid peptides and proved the activity against fire blight
agent Erwinia amylovora, halo blight agent Pseudomonas
syringae and bacterial spot agent Xanthomonas vesicato-
ria. Recently, it was determined that five AMPs, includ-
ing RW- BP100, CA- M, 3.1, D4E1 and Dhvar- 5 were good
candidates against E. amylovora (Mendes et al., 2021).
Vila- Perelló et al. (2003) reported the antimicrobial ac-
tivity of D32R, an analog of Pyrularia pubera thionin,
against the pathogenic fungi Fusarium oxysporum,
Plectosphaerella cucumerina and Botrytis cinerea, and
bacteria Xanthomonas campestris pv. translucens and
Clavibacter michiganensis.
The recombinant expression of AMPs in plant bodies
has been demonstrated as a successful approach that pro-
vided a certain degree of resistance to phytopathogens in
various transgenic plants. For example, Alf- AFP defensin
and a dermaseptin B1 derivative MsrA2 were expressed in
the potato against Verticullum dahliae and Pectobacterium
carotovorum, respectively (Gao et al., 2000; Osusky et al.,
2005). Mj- AMP1 jalapa defensin provided certain pro-
tection against Alternaria solani in transgenic tomatoes
(Schaefer et al., 2005). The expression of horseshoe crab-
derived tachyplesin I, in tobacco plants provided resis-
tance to the fungal pathogen Verticullum dahliae and the
phytopathogen Erwinia carotovora (Allefs et al., 1996).
Similarly, a synthetic polyphemusin variant PV5 showed
broad- spectrum enhanced resistance against a variety
of bacteria (E. carotovora, Staphylococcus epidermidis,
Bacillus subtilis and E. coli), fungi (Fusarium oxysporum
and Botrytis cineria) and virus (Tobacco Mosaic Virus)
in the transgenic tobacco plant (Bhargava et al., 2007).
The expression of cecropin P1, a mammalian antimicro-
bial peptide, in transgenic tobacco provided an increased
resistance towards the pathogenic bacteria P. syringae,
Pseudomonas marginata and E. carotovora (Zakharchenko
et al., 2005). In several studies focused on MSI- 99, an ana-
logue of magainin was expressed in different plants, such
as tobacco, banana, tomato and grapevine, which demon-
strated effective protection against a variety of fungal and
bacterial phytopathogens (Alan et al., 2004; Chakrabarti
et al., 2003; Vidal et al., 2006). In another study, Dm-
AMP1, a defensin from Dahlia merckii, was expressed in
the aubergine plant to protect against B. cinerea and V. al-
boatrum (Turrini et al., 2004).
In recent years, AMPs have drawn attention as a good
alternative for controlling post- harvest decay as well as
controlling plant diseases. The phytopathogens are im-
portant reasons for postharvest decays, resulting in sig-
nificant economic losses by declining quality or leading
deterioration in agricultural products (Keymanesh et al.,
2009). For instance, it was reported that the derived pep-
tide KYE28 from heparin cofactor II successfully inhibited
symptoms of spot disease caused by Xanthomonas vesica-
toria and Xanthomonas oryzae in separated tomato leaves
(Datta et al., 2016). In another study, the antifungal ef-
fects of O3TR (H- OOWW- NH2) and its lipopeptide deriv-
ative C12O3TR (C12- OOWW- NH2) were evaluated against
the green mould agent Penicillium digitatum, one of the
main post- harvest pathogens in citrus. Both in vitro and
in vivo studies showed that the O3TR and C12O3TR pep-
tides successfully controlled P. digitatum in citrus plants
(Li et al., 2019). Vase water contains various spoilage bac-
teria, shorting the vase life of roses after harvest. In a study
performed by Florack et al. (1996), it was found that tachy-
plesin I and cecropin B were highly effective against the
|
17
ERDEM BÜYÜKKIRAZ AND KESMEN
pure cultures of Bacillus, Enterobacter and Pseudomonas
species typically found in vase water. Datta et al. (2015)
showed that the external application of de novo designed
VG16KRKP peptide in both rice and cabbage plants could
effectively prevent the Gram- negative plant pathogens,
X. oryzae and X. campestris that cause bacterial diseases.
These last experiments show the potential of AMPs in the
control of important pathogens in the postharvest stage.
However, further studies are needed to examine the sta-
bility and economic feasibility of various peptides in de-
laying post- harvest decay and inhibition of plant diseases.
CONCLUSION
AMPs are basic elements of innate immunity in living or-
ganisms, which act rapidly and are multifunctional. Today,
studies for the detection of new AMPs from various sources
are increasingly continuing. Intensive research is being
carried out in order to convert the discovered AMPs into
commercial products and find new application areas. All
living organisms, particularly marine organisms are infinite
sources of AMPs. AMPs emerged as promising agents to be
able to meet the need for new antimicrobial compounds.
Although studies to date have indicated that AMPs have a
lower tendency to resist than antibiotics, it should not be
forgotten that this evolution is an inevitable consequence.
The limitations such as efficacy, stability and toxicity as-
sociated with natural AMPs are well- known drawbacks
that restrict the comprehensive utilization of AMPs. The
synthetic AMPs produced by de novo design offer prom-
ising progress at a certain level to eliminate these chal-
lenges. Even though it is easy to change the characteristics
of AMPs with minor modifications, the results of these
changes are still difficult to predict. Therefore, recently,
computational approaches have been introduced to AMP
research to understand the effects of structural modifica-
tions on the physicochemical properties, stability and activ-
ity of AMPs. These approaches also help to understand the
action mechanism of AMPs better and accurately predict
their activities. Apart from this, it is clear that the legal reg-
ulations of AMPs should proceed in line with all this effort.
CONFLICT OF INTEREST
None of the authors declare a conflict of interest.
ORCID
Zülal Kesmen https://orcid.org/0000-0002-4505-6871
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How to cite this article: Erdem Büyükkiraz, M. &
Kesmen, Z. (2021) Antimicrobial peptides (AMPs):
a promising class of antimicrobial compounds.
Journal of Applied Microbiology, 00, 1– 24. https://
doi.org/10.1111/jam.15314
