International Journal of Peptide Research and Therapeutics

https://doi.org/10.1007/s10989-020-10127-2

Human Antimicrobial Peptides: Spectrum, Mode of Action

and Resistance Mechanisms
Bibi Sedigheh Fazly Bazzaz1,2 · Shabnam Seyedi3 · Narjes Hoseini Goki3 · Bahman Khameneh2 

Accepted: 22 October 2020

© Springer Nature B.V. 2020

Abstract
Overuse of antibiotics is one of the important factors that contribute to developing antimicrobial resistance. Many studies
have been conducted to find out promising solutions to overcome the problems. Antimicrobial peptides (AMPs) are funda-
mental components of human innate immunity. They have an important role in the treatment of a wide range of diseases,
including cancer, allergies, and also in warding off invading pathogens. In the case of infectious disease, the AMPs exhibit
broad-spectrum activity against a wide range of pathogens including Gram-positive and -negative bacteria, yeasts, fungi, and
enveloped viruses. These peptides have been isolated from various sources such as microorganisms, plants, invertebrates,
and vertebrates. The peptides show distinct physicochemical and structural properties but most of them are small cationic
peptides with amphipathic properties. In this review, an overview of the classification, antimicrobial activities, mode of
action, and mechanism of resistance of human AMPs will be provided. These peptides are categorized into three main
groups. The defensins are cationic peptides containing six cysteine residues with three intramolecular disulfide bridges.
In humans, two classes of defensins could be found, α-defensins and β-defensins. The second group is cathelicidins that
only one AMP, LL-37, has been found in humans. This peptide is derived from proteolytic digestion of the C-terminal of
human CAP18 protein. The third group is the family of histatins that are small cationic histidine-rich peptides, and mainly
present in human saliva. The last two groups have random coil conformation in hydrophilic environments and α-helices in
a hydrophobic environment.

Keywords  Human antimicrobial peptides · Antibiotic resistance · LL-37 · Histatins · Defensins

Introduction
Antibacterial resistance by multidrug-resistant (MDR) path-
ogens has become a global health challenge and threatens
the health of societies. The emergence of resistant infections
leads to existing antibacterial drugs becoming less effective
or even ineffective and therefore, there is an urgent need
for the development of new antibacterial agents (Khameneh
et al. 2016). The death by drug-resistant bacterial infections
* Bahman Khameneh
Khamenehbagherib@mums.ac.ir
1
Biotechnology Research Center, Pharmaceutical Technology
Institute, Mashhad University of Medical Sciences,
Mashhad, Iran
2
Department of Pharmaceutical Control, School of Pharmacy,
Mashhad University of Medical Sciences, Mashhad, Iran
3
School of Pharmacy, Mashhad University of Medical
Sciences, Mashhad, Iran
in each year for USA, EU, and India was 23,000, 25,000, and
58,000, respectively (Chaudhary 2016). Additionally, with-
out developing novel approaches to combat MDR pathogens,
many fields of medicine such as surgery, cancer chemother-
apy, and transplantation medicine will be affected severely
(Worthington and Melander 2013). Whenever the antibac-
terial resistance has emerged, the problem has been tackled
with various approaches such as repurposing non-antibiotic
drugs, modification of the existing antibiotic classes with
limited cross-resistance, developing new classes of anti-
biotics, antibiotic combinations, development of adjuvant
therapy, developing a novel formulation of antibiotic, and
using natural compounds (Bazzaz et al. 2019; Farhadi et al.
2019; Khameneh et al. 2015a, 2019a, b; Soheili et al. 2019;
Theuretzbacher et al. 2020).
During the past years, the efforts for discovering the
novel antimicrobial agents have been focused on develop-
ing groups of short polypeptides, up to 40 residues, namely
antimicrobial peptides (AMPs) (Fox 2013; Javia et al. 2018).

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AMPs can be obtained from both natural and synthetic
sources and show a broad spectrum of targeted organisms
including viruses to parasites (Bahar and Ren 2013; Zasloff
2002). These peptides are categorized based on different
properties such as similarities in charge, sequence, func-
tional and 3-dimensional structure. Based on the charge of
AMPs, they are grouped into anionic and cationic peptides.
Anionic ones are small peptides (721.6–823.8 Da) and pre-
sent in bronchoalveolar lavage, fluid surfactant extracts, and
airway epithelial cells, while, cationic peptides are mainly
found in all living species. These latter AMPs contain 12–50
amino acid residues with a net positive charge of + 2 to  + 7.
They have an excess of basic amino acid residues such as
arginine, lysine, and histidine in comparison with acidic resi-
dues. Cationic AMPs have a diverse range of cellular targets
(Bahar and Ren 2013; Brogden et al. 2003; Bulet et al. 2004;
Huang et al. 2010).
AMPs show their antimicrobial properties via different
mechanisms. They showed weak antimicrobial actions but
have wide and strong immune-modulatory properties. Taken
together, they have been considered as alternative agents for
traditional antibiotics. AMPs have been successfully used
against resistant infections such as infectious biofilm or
MDR bacteria (Boparai and Sharma 2020; Park et al. 2011).
In contrast to an antibiotic peptide that is synthesized
through a specific metabolic pathway, the amino acid
sequence of AMPs is encoded naturally by the genetic
materials of the host organisms (Boparai and Sharma 2020).
Upon pathogen invasion, transcription and translation pro-
cesses are started and followed by post-translational modi-
fications including precursor protein cleavage, C-terminus
amidation, and disulfide bond formation for approximately
50% of the known AMPs. Moreover, glycosylation modifi-
cation may happen in uncommon cases (Toke 2005). These
AMPs were first detected in plant organisms, then in a wide
range of other organisms like humans (Toke 2005). So far,
the number of detected AMPs has reached more than one
million (Boparai and Sharma 2020).
AMPs show a broad variety of secondary structures
like β-strands, α-helices with extended structures, loops,
and one or more disulfide bridges (Edwards et al. 2017;
Hwang and Vogel 1998). These observed structural differ-
ences are necessary for their antimicrobial activities in a
broad spectrum (Hancock 2001). Additionally, particular
crucial factors like peptide self-association to biological
membranes, amphipathic stereo-geometry, hydrophobic-
ity, charge, and also size contribute to their antimicro-
bial activities (Boparai and Sharma 2020). Moreover, the
smaller size of antimicrobial peptides facilitates the fast
secretion and diffusion of peptide outside the cells that is
important for inducing defense responses against patho-
genic fungi and bacteria (Brogden 2005). This article aims
to review the classification of AMPs based on the structure
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International Journal of Peptide Research and Therapeutics
and composition and their mode of action. Moreover, the
essential aspects of human AMPs that have revealed their
significance will be discussed.
Classification of AMPs
Knowing about the three-dimensional structure of AMPs
leads to a better understanding of their mode of actions.
Nuclear magnetic resonance (NMR) has been used exten-
sively for analyzing the structures of most of the AMPs.
Because of the small size of AMPs in comparison with other
biopharmaceuticals, the three-dimensional structures could
be obtained by conventional two-dimensional NMR methods
(Reddy et al. 2004; Zhang and Falla 2006). Based on the
NMR data, AMPs could be classified into five groups.
α‑Helical AMPs
Abundant classes of AMPs are those with amphipathic
properties that have α-helical domains. Their particularly
successful structural arrangements help them for innating
defense. Most of them are short (< 40 residues) and there-
fore can be synthesized easily. Because of the structure, they
can be characterized by circular dichroism (CD) or NMR
spectroscopies, simply. It should be noted that these types of
AMPs are active against a wide range of pathogens, includ-
ing both Gram‐positive and ‐negative bacteria, fungi, and
protozoa (Giangaspero et al. 2001; Reddy et al. 2004). Some
of them are illustrated in Fig. 1.
Cysteine‑Rich AMPs
Cysteine-rich AMPs are diverse and widely distributed in
animal and plant tissues. They have an important role in host
defense systems (Dimarcq et al. 1998). The human neutro-
phil peptides HNP-1, -2, and -3 were the first of these AMPs
which isolated from the human granules (Ganz et al. 1985).
These α-defensins compose of 30 amino acid residues which
are rich in cysteine and could be found in a wide variety of
organisms (Reddy et al. 2004). Most of these AMPs contain
six cysteine residues and all of them participate in forming
three intramolecular disulfide bonds (Dimarcq et al. 1998).
These disulfide bridges are mostly between C1–C4, C2–C5,
and C3–C6 (Dimarcq et al. 1998; Hill et al. 1991). Based
on the NMR data, α-defensin has three-stranded antiparal-
lel β-sheets (Pardi et al. 1992). Some of them are illustrated
in Fig. 2.
International Journal of Peptide Research and Therapeutics
Fig. 1  Some examples of
α-helical antimicrobial peptides
Fig. 2  Some examples of
cysteine-rich antimicrobial
peptides
β‑Sheet AMPs
The third group of AMPs is peptides with β-sheets struc-
ture. Most of them are further stabilized by one or more
disulfide bonds. Based on their cysteine content and struc-
tural properties, they can be divided into two groups: (i)
β-hairpin peptides; and (ii) α-defensin peptides (Koe-
hbach and Craik 2019). β-hairpin peptides encompass
approximately 20 residues containing one or two disulfide
bonds. Examples of β-hairpin peptides are Horseshoe
crab (Limulus polyphemus) peptides, tachyplesins, and
polyphemusin II, which are stabilized via two disulfide
bridges; thanatin from insects (one disulfide bond); and
protegrin-1, peptides isolated from porcine leukocytes.
These molecules form an antiparallel β-sheet connected
to a β-turn and are composed of disulfide bonds (Kawano
et al. 1990; Tamamura et al. 1993). As shown by NMR
studies, lactoferricin B, containing 25 amino acids,
presents a β-sheet structure that stabilized by a single
disulfide bridge (Hwang et al. 1998). Some of these AMPs
are illustrated in Fig. 3.
13

Fig. 3  Some examples of
β-sheet antimicrobial peptides
AMPs Rich in Regular Amino Acids
Some of the AMPs contain high numbers of regular amino
acid residues and therefore their structures are different from
the regular α-helical or β-sheet peptides. For example, hista-
tin, a peptide isolated from human saliva is histidine-rich
AMPs and also effective against Candida albicans (Xu et al.
1991). Cathelicidins, a family of endogenous AMPs, are
proline-rich and show irregular structures (Tomasinsig and
Zanetti 2005). Indolicidin, a cationic AMP that consists of
only 13 amino acids, has the highest tryptophan content, and
tritripticin like indolicidin is rich in tryptophan (Bacalum
et al. 2017; Falla et al. 1996). Bactenecins are a class of
arginine-rich AMPs of bovine neutrophil granules (Ciociola
et al. 2018).
AMPs with Unnatural Amino Acids
Some of the AMPs contain unnatural amino acids such as
peptides from bacteria themselves. Nisin, a lantibiotic, is a
notable example of AMPs from this group. It is produced
by Lactococcus lactis and contains rare amino acids like
lanthionine, 3-methyllanthionine, dehydroalanine, and dehy-
drobutyrine (de Vos et al. 1993; Zhang et al. 2014). Nisin Q,
consisting of 34 amino acids, is a ribosomally-synthesized
AMP and contains post-translationally modified residues
such as lanthionine and dehydroalanine (Fukao et al. 2008).
Leucocin A is another peptide that composes of 37 amino
acids and isolated from Leuconostoc gelidum. It can form
an amphiphilic conformation and could interact with cell
membranes (Fregeau Gallagher et al. 1997). These AMPs
undergo post-translational modifications and after that, their
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International Journal of Peptide Research and Therapeutics
conformations could not see in other classes of AMPs. For
example, subtilin is a ribosomally synthesized AMP that
composes of several unusual amino acids as a result of post-
translational modifications (Liu and Hansen 1993). Gramici-
din is another example that contains several DH-amino acids
that result in forming an unusual cyclic β-hairpin (Gibbs
et al. 1998). Cbf-14, derived from cathelicidin-BF, is effec-
tive against antibiotic-resistant bacteria. In this AMP, lysine
or leucine was substituted with similar unnatural amino
acids such as ornithine (Orn) and norleucine (Ile) to gener-
ate AMPs with enhanced antibacterial activities. The data
indicated that the mutant of Cbf-14 possesses potent anti-
bacterial activities against penicillin-resistant bacteria (Kang
et al. 2017).
The Mode of AMPs Action
It was shown that the main mechanism of AMPs is pre-
sumably to include the establishment of membrane pore or
ion channel, without stereo-special interactions with chiral
receptors (Toke 2005). These observations were also con-
firmed by others that showed D enantiomers of melittin,
magainin 2 amide, and cecropin A were assayed and discov-
ered to show the identical hemolytic and antibacterial effica-
cies as their L counterparts that naturally occurred. Further-
more, the compounds all generated one channel conductance
in lipid bilayers, with the L, as well as D analogs, inducing
the identical extent of conductivity (Boparai and Sharma
2020; Wade et al. 1990). AMPs attain dynamic interchanges
in their topologies and structures upon interacting with cell
membranes in microorganisms (Sansom 1998).
International Journal of Peptide Research and Therapeutics
The outer surface of eukaryotic cells is composed of
sphingomyelin phospholipids and zwitterionic phosphati-
dylcholine, whereas the outer surface of prokaryotic cells
is negatively charged, because of the existence of teichoic
acid or lipopolysaccharides (Dolis et al. 1997). The elec-
trostatic interactions of AMPs with the negatively charged
molecules on membranes seem to be the preliminary mecha-
nism responsible for antimicrobial activities (Boparai and
Sharma 2020). AMPs apply their activities in host cells
through translocating across the cell membranes and pre-
vent fundamental cellular processes like cell wall synthe-
sis, enzymatic activities, as well as nucleic acid and protein
synthesis (Brogden 2005). Particular other factors like outer
membrane fluidity, molecular architecture, the concentration
of negatively charged molecules, as well as outer membrane
charge and magnitude also are important for the transport of
AMPs across the biological membranes (Kondejewski et al.
1999). The membrane fluidity was determined to regulate
the insertion and adsorption of antimicrobial peptides into
the cell membranes.
According to the mechanisms of action, AMPs are
classified widely into non-membrane acting and mem-
brane acting peptides. Three mechanisms were suggested
for pore-forming by membrane acting peptides (Boparai
and Sharma 2020). The barrel-stave mechanism refers
to insert AMPs into the biological membrane hydropho-
bic substance that flip inward and create pores through
producing trans-membrane helical bundles (Peters et al.
2010). In the carpet-like mechanism, AMPs destruct the
cell membranes assembly via their collaborative activity.
In this path, AMPs self-associate onto the acidic phospho-
lipids-rich areas located at lipid bilayer, and as soon as
their concentrations approach specific thresholds, they can
permeate into biological membranes. This phenomenon is
facilitated via escalating in the positive potential of lipid
bilayers (Mookherjee and Hancock 2007). Toroidal refers
to build toroidal pore in a lipid bilayer by the AMPs. Pore
constructions are administrated through the helix bundles
and lipid polar head groups, which vertically orient to the
Fig. 4  The pore-forming
mechanisms of antimicrobial
peptides
external section of membranes. In other words, the AMPs
cumulate and impel the lipid monolayers for continuous
bending through the pore so that both lipid head groups as
well as inserted peptides line the water core (Rahnamaeian
2011). The related mechanisms were illustrated in Fig. 4.
The permeabilizing non-membrane peptides are mostly
represented by the capability for translocating across the
cell membranes without permeabilizing the membrane,
whereas the permeabilizing membrane peptides are cati-
onic peptides with the ability to form the transient pores
on the biological membranes (Pushpanathan et al. 2013).
Particular AMPs inducing trans-membrane pores on the
membrane of target cells comprise LL-37 (Harder et al.
2007), magainins (Hallock et al. 2003), melittin (Yang
et al. 2001), and defensin (Schneider et al. 2005a). AMPs
like mersacidin (Brotz et al. 1995), pyrrhocidin (Kragol
et al. 2001), indolicidin (Friedrich et al. 2001), pleuro-
cidin (Patrzykat et al. 2002), HNP-1 (Lee et al. 2002),
dermaseptin (Patrzykat et al. 2002), and buforin II (Park
et al. 2000) get translocated across the biological mem-
branes and suppress important cellular processes that
result in cells death. Besides, some AMPs like lactofer-
rin (Patrzykat et al. 2002), histatin (Kavanagh and Dowd
2004), melittin (Park and Lee 2010), and papiliocin
(Hwang et al. 2011) apply their antimicrobial activity by
the formation of reactive oxygen species.
Human AMPs
Human AMPs protect the human from microbial infec-
tion by various mechanisms. They have been identified
in a variety of tissues or surfaces such as eyes, skin, ears,
mouth, lungs, intestines, and also the urinary tract (Wang
2014). Some of the most important ones with more details
are summarized here. Some important features of these
AMPs are summarized in Table 1.
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Table 1  Some important features of human antimicrobial peptides
AMPs family Structure
13
α-Defensins β-Sheet structure, with six
cysteine residues, form
three intramolecular
disulfide bonds, arginine-
rich peptides
β-Defensins β-Sheet structure, with six
cysteine residues, form
three intramolecular
disulfide bonds
Human cathelicidin Simple, linear, amphipathic,
cysteine-free α-helices
structure
Name Source
HNP (1–4) Neutrophils, late promyelo-
cytes, bone marrow, some
surface epithelial cells,
intestinal epithelial cells
(The female reproductive
tract)
HD 5,6 Intestinal Paneth cells
Paneth cells of the normal
duodenum, jejunum, and
ileum
hBD-1 Leukocytes and epithelial
cells, keratinocytes
hBD-2 Leukocytes and epithelial
cells, keratinocytes, the
gingival mucosa, and the
tracheal epithelium
hBD-4 Epithelia and in neutrophils,
neutrophils and the epi-
thelia of the thyroid gland,
the lung, the uterus, and
the kidney, testis and the
gastric antrum
LL37 The large variety of cells
(neutrophils,
leukocytes and epithelial
cells, Myelocytes, meta-
myelocytes, etc.), tissues,
body fluids, and profes-
sional phagocytes
Active against
Gram-negative and Gram-
positive bacteria (Both
intracellular and extracel-
lular organisms), Fungi,
yeast, viruses, parasites
Their spectrum of activity is
similar to that of neutrophil
defensins
Poor antibacterial activity,
antiviral against HIV, and
antifungal activity
Gram-negative and Gram-
positive bacteria
Fungi, yeast, antiviral against
HIV viruses
Weak antimicrobial activity
against E. coli, S. cerevi-
siae, S. aureus, S. pneu-
moniae, and B. cepacea,
and strong antimicrobial
activity against S. carnosus
and P. aeruginosa
Gram-positive and Gram-
negative bacteria fungi,
and virus (Only little viral
inactivation: herpes sim-
plex virus) and parasitic
pathogens, the yeast cell
Mode of action References
Mainly membrane per- Agerberth and Guðmundsson
meabilization and disrupt (2006), Cunliffe (2003), De
bacterial membranes Smet and Contreras (2005),
Ganz (2001), Schneider
et al. (2005)
‘Carpet model’, bind to Agerberth and Guðmunds-
the negatively charged son (2006), De Smet and
cytoplasmic membranes Contreras (2005), Pazgier
and disrupt their integ- et al. (2006a), Schneider
rity, leading to leakage of et al. (2005)
intracellular components
and also inhibit the DNA,
RNA, and protein synthe-
sis or form channel-like
pores spanning across the
membranes
Membrane perturbation (The Agerberth and Guðmunds-
barrel stave model and the son (2006), De Smet and
carpet model), detergent- Contreras (2005), Dürr et al.
like effect, non-pore (2006), Lee et al. (2011),
carpet-like mechanism, Neville et al. (2006), Oren
transmembrane pores et al. (1999), Thennarasu
induced et al. (2010)
International Journal of Peptide Research and Therapeutics
 International Journal of Peptide Research and Therapeutics

Human Defensins

(2017b), Shah et al. (2016)

(2005), Kalmodia et al.
(2019), Khurshid et al.
De Smet and Contreras α-Defensins were the first human group of AMPs to be
characterized which were isolated from human blood.
They are mostly cationic peptides containing between
29 and 35 amino acid residues. They have six cysteine
References

residues that form three disulphide bonds. The cysteine

bridges are between C1–C6, C2–C4, and C3–C5 that form
cyclic peptides with a typical structure of a triple-stranded
β-sheet and a β-hairpin loop (Ryley 2001; Wang 2014).
ing to the Trk1 potassium
against bacteria and viruses to the loss of intracellular

potassium ions (via bind-

membrane and releasing

Based on the source, property, and size, these peptides

membrane, which leads
Disruption of the plasma

components. For yeast

cell by damaging the

α-defensins are categorized into four groups: (I) HNP-1,

HNP-2, and HNP-3; these three AMPs have almost iden-
Mode of action

tical amino acid sequences. In comparison with HNP-2,

transporter)

HNP-1 and HNP-3 contain only one additional residue at

the N-terminus: alanine in HNP-1 and aspartate in HNP-
3. (II) The fourth human neutrophil defensin, HNP-4, has
a distinct peptide sequence with 33 amino acid residues.
(III) HD-5 was obtained from human Paneth cells and
Especially active against

present in the female reproductive tract. (IV) HD-6 ones

fungi but also active

are only expressed in the Paneth cells of human intestines

(Schneider et al. 2005; Wang 2014). The human β-defensin
Active against

family (hBD) was different from α-defensins. The disulfide

bonds of β-defensins are between C1–C5, C2–C4, and
C3–C6. Also, these AMPs have a slightly longer sequence
than α-defensins that leads to form an additional helical
region. The related structures are illustrated in Fig. 5.
Histatin 1, 3, 5 Salivary glands (parotid and
submandibular glands)

Spectrum of Activity

They are active against a wide spectrum of both Gram-

Source

positive and -negative bacteria, mycobacteria, fungi, and

some enveloped viruses (Winter and Wenghoefer 2012).
For example, at concentrations higher than 100 μg/ml,
HNP-1 and HNP-2 could kill the bacteria, including both
Name

intracellular and extracellular microorganisms (Lehrer

et al. 1993). HNP-1 exerts potent in vitro microbicidal
activity against a wide range of human pathogens, such
Small, cationic, histidine-

as Staphylococcus aureus. Based on the evidence, HNP-1

could target and disrupt the bacterial membrane (Xiong
rich polypeptides

et al. 1999). HNP1–4 and HD-5 show antibacterial activi-

ties against Gram-positive bacteria, such as S. aureus, and
also Gram-negative bacteria as Enterobacter aerogenes
Structure

and Escherichia coli (Ericksen et al. 2005). HNP1 was

also highly effective against Mycobacterium tuberculosis
(Sharma et al. 2000, 2001). HNP1–3 by binding to the
Table 1  (continued)

lethal factor of the anthrax pathogen, Bacillus anthracis,

was able to inhibition of its enzymatic activity (Verma
AMPs family

et al. 2007). HD-5 shows potent antimicrobial activities

Histatins

against a wide range of pathogens such as E. coli, Listeria

13

Fig. 5  The related structures of
human defensins
monocytogenes, Salmonella typhimurium, and C. albi-
cans, whereas minimal inhibitory concentration (MIC)
values are in the nanomolar range (Porter et al. 1997).
hBD-1, -2, -3 showed antibacterial activities against E.
coli and S. aureus in a dose-dependent manner (Chen et al.
2005). hBD-3 showed a broad spectrum of antimicrobial
activities against different pathogenic microbes such as
multiresistant S. aureus, vancomycin-resistant Enterococ-
cus faecium, Pseudomonas aeruginosa, Klebsiella pneu-
monia, Streptococcus pneumoniae, and Burkholderia
cepacia. This AMP has also antifungal activities against
Candida glabrata and synergistic effects with fluconazole
were observed (Dhople et al. 2006; Harder et al. 2001;
Inthanachai et al. 2020; Pazgier et al. 2006b). The in vitro
activities of hBD-3 alone or combined with other antimi-
crobial agents were investigated and the results showed
that it was effective against Streptococcus mutans, Strep-
tococcus sanguinis, Streptococcus sobrinus, Lactobacillus
acidophilus, and Porphyromonas gingivalis. The bacte-
ricidal activities were enhanced in combination with the
antimicrobial agents (Maisetta et al. 2003). Antimicrobial
effect of hBD-4 on Fusobacterium nucleatum and P. gingi-
valis has been studied and the results showed antibacterial
activity (Zhai et al. 2019). hBD‐4 exhibits potent anti-
bacterial activity against P. aeruginosa (MIC = : 4.1 μg/
ml) (Garcia et al. 2001). These AMPs also showed the
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International Journal of Peptide Research and Therapeutics
anti-viral activities and at natural levels they could provide
a minimal level of defense against viral infections (Park
et al. 2018).
Mechanism of Action
It was assumed that the antibacterial activities the defensins
are composed of a two-stage mode of action. It should be
noted that there is the same mechanism of action for both
types of defensins. At first, they bond to the outer membrane
of the bacteria that leads to access to the inner (cytoplas-
mic) membrane. Then, by internalization into the cytoplas-
mic membrane, they form channels in the bacterial surfaces
(Ryley 2001).
In more detail, these AMPs interact with the divalent cati-
onic binding sites such as ­Ca2+ and ­Mg2+ in the lipopolysac-
charide of bacterial surface and displacing these cations.
In the case of Gram-positive bacteria, AMPs could interact
with the anionic lipoteichoic acid of the cell resulting in
access to the cytoplasmic membrane (Malanovic and Lohner
2016). It should be noted that the size of AMPs has direct
influences on the distortion of the outer layer and then access
to the underlying cytoplasmic layer (White et al. 1995).
The second stage is similar for both Gram-positive and
-negative bacteria. The cationic residues interact with the
International Journal of Peptide Research and Therapeutics
negatively charged membrane and then because of high elec-
trical potential, the AMPs being inserted into the membrane.
Following the aggregation of AMPs in the membrane, they
could form the channels, and finally, leads to membrane per-
meabilization and disruption (Ryley 2001).
Mechanism of Bacterial Resistance
The mechanisms of antibacterial resistance are poorly under-
stood, however, it was assumed that changing in LPS struc-
ture leads to make it less susceptible to AMPs, and therefore
binding of peptides is restricted and antibacterial resistance
will be developed (Ryley 2001).
Cathelicidins
Cathelicidins, along with defensins belong to the group of
cationic AMPs with amphipathic properties and recognize
as an integral part of the immune system (De Smet and Con-
treras 2005). They are mainly stored in neutrophil and mac-
rophage granules and show a direct antimicrobial activity
against a wide range of microbial pathogens via the oxygen-
independent activities (Bals and Wilson 2003; Tomasinsig
and Zanetti 2005). Despite a large number of  cathelici-
din family members in animals, to date, only a single catheli-
cidin, LL-37, has been known in humans (Ryley 2001). This
AMP is encoded by the cathelicidin gene (CAMP) which is
composed of 39 residues, two leucine residues at N-terminal,
and 37 residues long and has a molecular weight of 18 kDa
(Agerberth et al. 1995). Subsequently proteolysis of the pre-
cursor, possibly by elastase digestion, in the neutrophil and
missing the terminal residues, a 37 amino acid peptide was
released and consequently termed LL-37 (Gudmundsson
et al. 1996).
LL-37 has an α-helix structure that lacks cysteine. There-
fore, it has a linear structure without disulphide bonds. It is
expressed in leukocytes such as neutrophils, monocytes, NK
cells, T cells, and B cells, and also, like hBD-2, in human
epithelial tissue such as testis, skin, and the gastrointestinal
and respiratory tracts in the presence of inflammation and
is possibly related to the interleukin-6 production (De Smet
and Contreras 2005; Frohm Nilsson et al. 1999).
Spectrum of Activity
LL-37 shows a wide spectrum of antibacterial activities
against both Gram-positive and negative bacteria, with the
MIC values lower than those of defensins (Turner et al.
1998). However, unlike defensins, it presents little activ-
ity against C. albicans or herpesviruses. This AMP is also
inactive against some bacteria, like B. cepacia, that is natu-
rally resistant to cationic peptides (Ryley 2001). In vitro anti-
bacterial activities, LL-37 against Legionella pneumophila
was tested and the results indicated that the AMP displayed
broad-spectrum and in vitro activity against L. pneumoph-
ila (Birteksoz-Tan et al. 2019). Synergic enhancement of
activity was observed between LL-37 and alpha-defensin
against both E. coli and S. aureus (Nagaoka et al. 2000).
In a study, the antibacterial effects of this peptide were
evaluated against methicillin-resistant S. aureus (MRSA)
and multidrug-resistant P. aeruginosa. Additionally, the
antipseudomonal activities of colistin or imipenem com-
bined to LL-37 were also studied. The results of the study
revealed the rapid antibacterial effects of LL-37 against
both antibiotic susceptible and resistant bacterial strains.
When antibiotics were combined with LL-37, the MIC val-
ues of colistin and imipenem decreased up to eight-fold and
four-fold, respectively (Geitani et al. 2019). In a study, the
in vitro anti-Helicobacter pylori activity of LL-37 in simu-
lated gastric juice was assessed and the results showed that
after incubation the antibacterial activity was not retained
(Leszczynska et al. 2009). It was shown that LL-37 and
its fragments exerted antibacterial activities against drug-
resistant Acinetobacter baumannii strains. This AMP and
two of its fragments also could inhibit biofilm formation
by A. baumannii (Feng et al. 2013). Microscopy studies
show that the treatment of fluconazole-resistant Candida
strains with LL-37 causes Candida cells to undergo surface
changes that indicating surface membrane damage (Durnas
et al. 2016). LL-37 is also effective against mycobacteria and
can kill Mycobacterium smegmatis, Mycobacterium bovis
BCG, and Mycobacterium tuberculosis under in vitro growth
conditions, additionally, this AMP reduced the intracellular
survival of the mycobacteria remarkably (Sonawane et al.
2011).
Mechanism of Action
They act as antimicrobial agents by either directly killing the
pathogen or indirectly by binding to the bacterial exopoly-
saccharides, outer bacterial cell wall components such as
the lipopolysaccharide (LPS) layer in the Gram-negative or
the teichoic acids in the Gram-positive bacteria (Ramana-
than et al. 2002; Xhindoli et al. 2016). Amphipathicity is an
important factor for effective antibacterial properties. This
attitude is more pronounced for α-helical cathelicidins such
as LL-37. These peptides can form ion channels or aque-
ous pores in the bacterial membrane and rapidly permeabi-
lize the membranes of microbial pathogens (Gennaro et al.
1998; Oren et al. 1999). Additionally, it was observed that
LL-37 could strongly bind to zwitterionic or acidic phos-
pholipid membranes of the vesicles and leads to leakage of
13

vesicular content (Oren et al. 1999). Then the peptide forms
quite sizeable toroidal pores. In more detail, at the first step,
LL-37 is electrostatically attracted by membranes followed
by assembly and partial integration. In the next step and after
full integration into the lipid bilayer, the peptide forms chan-
nels based on peptide-peptide and peptide-lipid interactions.
These interactions initiate the conformational changes and
the formation of fiber-like oligomers on the inner membrane.
The fibers lead to increasing the local concentration of the
peptide that finally will interfere with the bacterial mem-
brane stability. These transient pores allow the peptide to
translocate into the bacterium. At this site, the peptide may
interfere with internal targets such as DNA and also vital
processes such as transcription (Brogden 2005; Wang 2008;
Xhindoli et al. 2016). Moreover, in Gram-negative bacteria,
LPS may be translocated apart from the bacterial cell wall to
build holes for the LL-37 translocation into the periplasmic
space (Vandamme et al. 2012).
Mechanism of Bacterial Resistance
It was assumed that the changes in the structure of LPS
in Gram-negative bacteria affect the binding properties of
LL-37. For example, surface structures containing phos-
phorylcholine, a component of eukaryote cell membranes,
have been found in some respiratory pathogens such as Hae-
mophilus influenza. The Mutants that do not express this
structure were 1000-fold more sensitive to LL-37 than those
having this lipid in their membrane (Lysenko et al. 2000).
It was also shown that Neisseria gonorrhoeae has a type
of efflux pump system that can reduce the susceptibility of
the bacteria to LL-37 (Miyasaki et al. 1990). In Bordetella
pertussis, d-alanine incorporation induces resistance to
the AMPs. It was demonstrated that the dra operon of B.
pertussis is responsible for the d-alanylation of the outer
membrane component. Mutation in this operon results in
increasing sensitivity of bacteria to LL-37, and other AMPs
(Taneja et al. 2013).
Additionally, the antibacterial resistance against AMPs
might be due to the production of degradation enzymes such
as proteases AMPs. Bacterial strains can promote bacterial
resistance to the AMPs by their proteolytic degradation
properties (Abdi et al. 2019).
Histatin
Histatins are a family of cationic small AMPs that are largely
composed of histidine-rich repeats. They have a molecular
weight of about 3–4 kDa and are produced by the subman-
dibular, sublingual, and parotid glands and secreted into
human saliva (De Smet and Contreras 2005).
13
International Journal of Peptide Research and Therapeutics
These AMPs consist of several members, however,
among them, histatin 1, 3, and 5 are the most important ones.
They have linear structures and composed of 38, 32, and 24
amino acid residues for histatin 1, 3, and 5, respectively and
each of them contains seven histidine residues. Histatin 1
and 3 are encoded by two highly related genes, HIS1 and
HIS2, respectively and others are produced by the cleavage
of these two peptides. For example, histatin 5 was proteo-
lytic digestion of histatin 3 (Wang 2014). Histatin 5 has a
unique secondary structure. This AMP forms a random coil
structure in aqueous solvents while in non-aqueous solvents
the structure converts to α-helix (Helmerhorst et al. 1997;
Raj et al. 1998).
Spectrum of Activity
These peptides possess some bactericidal activities and,
more importantly, fungicidal properties. It should be noted
that of all histatins, histatin 5 has the strongest antimicrobial
activity, and most of the research on histatins has focused on
this peptide (Khurshid et al. 2016; Oppenheim et al. 1988).
The in vitro study indicated that histatin 5 could inhibit Can-
dida species (C. albicans, C. glabrata, C. krusei) at a certain
concentration (15–30 μM). It was also demonstrated that the
analog of histatin 3 with the shorter amino acid sequences
has the same candidacidal activity with respect to the full-
length molecule (Raj et al. 1990).
These AMPs possess their anti-fungal activities in differ-
ent ways such as growth inhibitory actions on C. albicans or
inhibition of the conversion of C. albicans yeast growth into
hyphal growth (Moffa et al. 2015).
The antimicrobial activities against other pathogens
Cryptococcus neoformans and Aspergillus fumigatus has
also been reported (Helmerhorst et al. 1999b). Also, hista-
tin 5 virucidal activity and only histatin 5 derived peptides
affect HIV-1 (Wang 2014). Inhibitory and bactericidal
activities of histatins have also been reported against various
bacteria, including S. mutans, P. gingivalis, P. aeruginosa,
E. coli, and S. aureus (Gusman et al. 2001; MacKay et al.
1984; Sajjan et al. 2001).
Mechanism of Action
Unlike other AMPs, it is well-known that all targets of
histatins are intracellular and the primary mode of actions
is not related to lyse lipid membranes (Puri and Edgerton
2014; Ryley 2001; Wang 2014). It has been found that the
massive non-lytic release of ATP along with the decrease in
intracellular ATP levels is the main mechanism of actions
of histatins (Helmerhorst et al. 1999a; Koshlukova et al.
1999). It was shown that histatin 5 could bind to the cell
International Journal of Peptide Research and Therapeutics
wall proteins and glycans of C. albicans and then is taken
up by the fungal polyamine transporters in the cells in an
energy-dependent manner. Inside the fungal cells, the AMP
may affect the mitochondrial functions and leads to oxidative
stress. However, cell death is the result of other processes
such as volume dysregulation and ion imbalance caused
by osmotic stress. Additionally, the metal-binding ability
of histatin 5 is the other mentioned mechanism (Edgerton
and Koshlukova 2000; Khurshid et  al. 2017a; Komatsu
et al. 2011; Puri and Edgerton 2014). Taken together, the
key steps in the histatin 5 antifungal activity involve a bio-
energetic collapse of C. albicans, consequently decreasing
the mitochondrial ATP synthesis.
The other reported fungistatic and fungicidal mechanisms
include disruption of the plasma membrane, which leads
to the loss of intracellular constituents (Oppenheim et al.
1988). It was also found that these AMPs were also effective
in killing the yeast cells by damaging their membranes and
releasing potassium ions. These effects were related to the
binding to the Trk1 potassium transporter and then the loss
of intracellular components (Swidergall and Ernst 2014).
The other modifications caused by histatin 5 in C. albicans
included organelles in disarray, intracellular membrane dis-
arrangement, and central cavities with deformed structures
displaced to the cell periphery (Isola et al. 2007).
It was found that the histatins, like other AMPs, could
interact with extracellular actin and the extracellular actin
might regulate histatin anti-fungal activities in the oral cav-
ity. In a study, it was demonstrated that both histatin 3 and
5 interact with actin, however, and affect the actin structure
(Blotnick et al. 2017).
Mechanism of Microbial Resistance
It was shown that cellular accumulation of the peptides is
necessary for anti-fungal activities and also that accumu-
lation of histatins depends on the availability of cellular
energy. Therefore, respiratory mutants of the microorgan-
isms which have undergone mutations in mitochondrial
DNA exhibited resistance against histatins (Gyurko et al.
2000). Therefore, it was assumed that the altered membrane
energetics is an important factor for developing resistance
(Yeaman and Yount 2003). Additionally, histatin 5 is trans-
ported out of C. albicans cells by the Flu1 and Mrr1 efflux
pumps (Hampe et al. 2017; Li et al. 2013). The multidrug
resistance transporters CgTpo1_1 and CgTpo1_2 have criti-
cal roles in the virulence of C. glabrata infections such as
resistance to histatin 5 (Santos et al. 2017). It was demon-
strated that the upregulation of CgCDR efflux pumps could
develop the resistance to histatin 5 in C. glabrata (Helmer-
horst et al. 2006).
AMPs Challenges
Although AMPs often present antibacterial activities,
own several unfavorable features for clinical applications,
including (I) the pharmacokinetic profiles of antimicro-
bial peptides are not well known, and only a few clinical
research have been performed with AMPs; (II) sensitivity
to proteolysis process derived by bacterial proteases; and
(III) cytotoxicity to the eukaryotic cell, which could result
in neurotoxicity, nephrotoxicity, and hemolysis (Craik
et  al. 2013; Grassi et  al. 2017). Nevertheless, several
types of research have been conducted for improving our
knowledge of the above-mentioned challenges (Chou et al.
2008). In comparison to conventional antibiotics, AMPs
are also expensive for being synthesized on mass scales
(Otvos and Wade 2014). Various strategies have been per-
suaded to overcome these limitations. For this scenario,
employing nanocarriers, developing pegylated AMPs, and
covalent immobilization of AMPs on surfaces have been
mentioned (Long et al. 2017; Manteghi et al. 2020).
Covalent attachment of the polyethylene glycol polymer
to peptides and proteins (PEGylation) could improve the
bioavailability of AMPs and enhance their pharmacoki-
netic properties such as bio-distribution and rate of clear-
ance. Additionally, the proteolytic degradation of AMPs
might be decreased by protecting their C- and N-terminus
(Gong et al. 2015; Gonzalez-Valdez et al. 2012; Khameneh
et al. 2015b).
The progress in nanotechnology has permitted various
nanoparticles to work as a favorable approach for minimiz-
ing the unfavorable features of synthetic as well as natural
AMPs (Umerska et al. 2017). The researchers have sug-
gested that AMPs in nanoparticles represent increased effi-
ciency, decreased degradation, and lower toxicity (Wang
et al. 2017). As a result, nanoparticles could contribute to
the manufacturing of AMPs and their applications in the
industry. Nano-carriers are considered as a drug delivery
system that presents many profits, like improvement of
drug pharmacokinetic profile, treatment selectivity, and
the protection of AMPs against extracellular degradations
(Sadat et al. 2016). Over the last 50 years, multiple drug
delivery systems have been used for encapsulating drugs
and other biomolecules, including polymeric nanopar-
ticles, dendrimers, micelles, and liposomes (Malaekeh-
Nikouei et al. 2020).
Nanobiotechnology has proposed two major proce-
dures to encapsulate AMPs. The passive delivery, as non-
directed procedures, includes traditional nano-delivery
systems that do not own surface modifications for guiding
the nano-carriers; this could be manipulated by control
the nano-carriers shape as well as size (Makowski et al.
2019). Active targeting, as directed delivery, includes
13

surface modifications of the nano-carriers with various
ligands and/or other moieties for permitting interaction
of nano-carriers and the target sites (Biswaro et al. 2018).
However, developing viable drug delivery systems for
clinical trials remains a challenge (Wimley and Hristova
2011). There are two procedures of nano-delivery systems
that have some advantages and disadvantages (Makowski
et al. 2019). Passive systems attend to own fewer agents in
their combination in contrast to active systems (Biswaro
et al. 2018). As passive systems possess fewer agents in
their combination, this causes it easier for preparing them
(Makowski et al. 2019). Besides, active systems contain
modified surface-carrying ligands and/or other moieties for
facilitating its interactions with infected cells and increase
the drug transports at such particular sites (Biswaro et al.
2018), while passive systems involve encapsulating pep-
tides without making available extra surface modifications
(Hunter et al. 2012). Given the above-mentioned, the terms
nano-delivery system as well as nano-carriers have been
suggested (Makowski et al. 2019).
Conclusion
Clinical overuse of antibiotics unavoidably results in the
growing emergence of drug-resistant strains of microbial
pathogens. Consequently, the development of a new class
of antibiotics is an urgent need. During the last decades,
considerable efforts have been conducted for investigating
the possible use of AMPs or synthetic derivatives as thera-
peutic antibacterial agents. They are implicated in several
biological processes, and also have an important role in the
innate immune system. The AMPs protect the host against
both systemic and topical infections either alone or in com-
bination with conventional antibiotics. Human AMPs are
an important class of these peptides which attract attention
for the treatment of various disease and some of them have
entered clinical trials for use in clinical applications such
as the treatment of diabetic ulcers as topical anti-infective
agents for the treatment of microbial infections. The ongo-
ing discovery and development of new AMPs are promis-
ing approaches in the fight against increasingly resistant
pathogens.
Author Contributions  BK collaborated in the original idea, concept,
design, and writing and drafting the article. SS and NHG contributed
with data interpretation, writing, and drafting of the article. BSFB
contributed to all stages of the process and mainly participated in draft-
ing the article, writing, and editing the final version to be published.
All the authors read and approved the final version of the manuscript.
Funding  The study was not funded by any authority.
13
International Journal of Peptide Research and Therapeutics
Data Availability  This review was based on data extracted from pub-
lished papers available in all relevant databases without limitation up
to 1st July 2020.
Compliance with Ethical Standards 
Conflict of interest  The authors declare that they have no competing
interests.
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