Saudi Pharmaceutical Journal 26 (2018) 396–409

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Saudi Pharmaceutical Journal

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Review

Recent updates of marine antimicrobial peptides

Mohammad H. Semreen a,⇑, Mohammed I. El-Gamal a,b,⇑, Shifaa Abdin a, Hajar Alkhazraji a,
Leena Kamal a, Saba Hammad a, Faten El-Awady a, Dima Waleed a, Layal Kourbaj a
a
College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
b
Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt

a r t i c l e i n f o a b s t r a c t

Article history: Antimicrobial peptides are group of proteins showing broad-spectrum antimicrobial activity that have
Received 27 November 2017 been known to be powerful agents against a variety of pathogens. This class of compounds contributed
Accepted 3 January 2018 to solving the microbial resistance dilemma that limited the use of many potent antimicrobial agents. The
Available online 4 January 2018
marine environment is known to be one of the richest sources for antimicrobial peptides, yet this
environment is not fully explored. Hence, the scientific research attention should be directed toward
Keywords: the marine ecosystem as enormous amount of useful discoveries could be brought to the forefront. In
Antimicrobial peptides
the current article, the marine antimicrobial peptides reported from mid 2012 to 2017 have been
Marine antimicrobial peptides
Antibacterial
reviewed.
Antifungal Ó 2018 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an
Antiviral open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Antiparasitic

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
2. Antibacterial marine peptide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
3. Antimycobacterial marine peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
4. Antifungal marine peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
5. Antiviral marine peptide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
6. Anitprotozoal marine peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408

1. Introduction 2004). The living organisms use the AMPs as an important vital
tool for survival. They combat the invading pathogens to the host
Antimicrobial peptides (AMPs) are molecules known to be via a broad spectrum of antimicrobial activity that can vary accord-
essential components of the innate immune response that can also ing to the nature of the pathogens (Lehrer et al., 1983; Ganz et al.,
participate in certain organisms as immune modulators (Zanetti, 1985; Zasloff, 1987). The wide spectrum is in part attributed to the
diversity in the structures of AMPs that vary from alpha helix to
beta strands (Hancock, 2001). AMPs play defensive role for the
⇑ Corresponding authors at: College of Pharmacy, University of Sharjah, Sharjah producing organisms. When it comes to their selective toxicity,
27272, United Arab Emirates (M.I. El-Gamal). the AMPs explore the differences in the lipid composition of the
E-mail addresses: [email protected] (M.H. Semreen), drmelga- membrane between eukaryotic and prokaryotic organism that
[email protected] (M.I. El-Gamal).
serves as their target of action sparing the host from harmful
Peer review under responsibility of King Saud University.
effects. Nevertheless, the selectivity of these molecules also rise
from the effect of the uniform net charge and hydrophobicity
which are characteristic trades for AMPs. The majority of these
compounds have been described to be carrying a uniform positive
Production and hosting by Elsevier

https://doi.org/10.1016/j.jsps.2018.01.001
1319-0164/Ó 2018 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 M.H. Semreen et al. / Saudi Pharmaceutical Journal 26 (2018) 396–409 397

charge ranging from +2 to +9, with only few reported to be anionic 2. Antibacterial marine peptide
in nature (Zasloff, 2002).
The cationic nature accounts for the AMPs mechanism of action, Almost there is no marine organism that does not produce nat-
as it enables their binding to the negatively charged lipopolysac- ural antibacterial compounds as an essential line of defense to sur-
charides invading pathogen membrane via electrostatic attractive vive, hence marine antibacterial peptides is a rich class of
forces. During this interaction, the AMPs acquire an amphipathic antimicrobials with new discoveries.
confirmation that optimizes the binding to the pathogen’s mem- Aurelin is an AMP derived from the mesoglea of a scyphoid jel-
brane. This kind of AMPs are classified to be membrane permeabi- lyfish called Aurelia aurita. It is composed of 40 amino acid residues
lizing peptides due to their capability of forming pores in the and described to be cationic in nature with a molecular weight of
membrane after their electrostatic interaction, thus resulting in 4296.4 Da. It has demonstrated modest antibacterial activity
expulsion of cellular content and subsequent cell death against both Gram-positive and Gram-negative bacteria with MIC
(Sengupta et al., 2008). In addition to the previously mentioned of 10 lM against the Bacillus megaterium, strain B-392, and 40
mechanism, AMPs can act by interfering with some vital cellular lM against Micrococcus luteus, strain Ac-2229 which were deter-
processes inhibiting them after their translocation across the cellu- mined to be the most sensitive species to Aurelin. Fig. 1 shows that
lar membrane. These peptides are classified as non membrane- Aurlein is the first AMP to acquire Shk fold that enables Aurelin to
permeabilizing peptides (Kondejewski et al., 1999; Brogden, 2005). have a diversity in its mechanism of action which can be attributed
AMPs nowadays are an interesting field of research for potential to two different mechanisms; (i) acting as a peptide toxin bocking
drug candidates owing to their broad spectrum of activity and K+ channels, (ii) acting as a membrane active antimicrobial peptide
more importantly to the fact that AMPs may overcome the antimi- (Shenkarev et al., 2012).
crobial resistance. Since AMPs target the lipid components in the Mytimacin-AF is an AMP derived from marine mollusks, partic-
membrane of the invading pathogens, this interference with such ularly from the mucus of Achatina fulica snail. It is characterized to
a vital structure in microbes creates a barrier against resistance be rich in cysteine as it is composed of 80 amino acid residues 10 of
development. This fact has directed the effort of scientific research which are cysteines, and its molecular weight is 9711.41 Da.
to exploit the vast world of AMPs where we can find more than Mytimacin-AF showed activity against both Gram-positive and
2000 AMPs reported in antimicrobial peptide databases [http:// Gram-negative bacteria, however it was most potent against Sta-
aps.unmc.edu/AP/main.php/]. phylococcus aureus with minimum inhibitory concentration (MIC)
Despite the promising activity of the AMPs, they suffer from the value of 1.9 lg/ml. In addition, the most promising feature about
following drawbacks. (i) limited stability at certain pHs; (ii) disrupt mytimacin-AF is its activity against the human Klebseilla pneumo-
the cellular membrane of eukaryotic organisms causing hemolytic nia, one of the most common hospital-acquired bacterial infec-
side effects; (iii) elevated production cost and technical issues are tions, what makes mytimacin-AF a very promising antibacterial
limitations of their manufacturing (Mygind et al., 2005); (iv) lack of agent (Zhong et al., 2013).
data on their toxicity, pharmacodynamics, and pharmacokinetics Myticusin-1 (TDHQMAQSACIGVSQDNAYASAIPRDCHGGKTCEGI
properties (Evans et al., 1999; Michalopoulos et al., 2005); (v) CADATATMDRYSDTGGPLSIARCVNAFHFYKRRGEENVSYKPFVVSW
reduced activity in the presence of some cations such as calcium, KYGVAGCFYTHCGPNFCCCIS) is another cysteine-rich peptide
iron and certain serum conditions (Smith et al., 1996; Thackray derived from mussels. It was characterized and identified from
and Moir, 2003). the hemolymph of Mytilus coruscus. Its involvement in the host
We have previously reviewed the chemical and biological prop- immune response has been proven, hence it plays a role in bacte-
erties of the marine AMPs reported from 2009 to June 2012 (El- rial infection eradication. The cysteine amino acid comprises 10
Gamal et al., 2013). Herein, we reviewed the very recent research out of 104 amino acid residues which makes myticusin 1 a long
results in the field of marine AMPs, which were characterized polypeptide chain with a molecular weight of 11,279.63 Da. This
and identified in the time period from July 2012 till 2017. We have molecule has demonstrated greater potency against Gram-
classified marine AMPs according to their biological effects into positive compared to Gram-negative bacteria, as it has recorded
antibacterial, antimycobacterial, antifungal, antiviral, and an MIC < 5 mM against a variety of tested Gram-positive strains
antiprotozoal. including S. aureus compared to an MIC >10 mM against a variety
of Gram-negative bacteria including E. coli (Liao et al., 2013).
EC-hepcidin3 (APAKCTPYCYPTHDGVFCGVRCDFQ), is a novel
isoform that belongs to the hepcidin class of AMPs. This class is
also known to be rich in cysteine, but this isoform is rather a four
cysteinehepcidine unlike the typical eight cysteinehepcidin. It was
cloned from the marine fish, the orange spotted grouper Epinephe-
lus coioides. The purified Ec–hepcidin 3 has a theoretical molecular
weight of 2798.2 Da. The kinetic studies proved that this molecule
has a rapid and strong antibacterial activity against Staphylococcus
aureus (MIC 1.5–3 lM, MBC 1.5–3 lM) and Pseudomonas stutzeri
(MIC < 1.5 lM and minimum bactericidal concentration (MBC)
< 1.5 lM) (Qu et al., 2013).
Marine’s bacteria are also important source for AMP,
Gageostatins A-C (Fig. 2). They are examples of three new non-
ribosomal lipopeptide molecules that were derived from the broth
of the bacterium Bacillus subtilis. These three molecules are consist-
ing of heptapeptides and new fatty acid which is 3 beta hydroxy
fatty acid and are anionic in nature with a uniform net charge of
3. Those molecules were tested as anticancer agents against a
Fig. 1. Spatial structure and backbone dynamics of aurelin in aqueous solution panel of six cancer cell lines; MDA-MB-231 breast cancer cell line,
(Shenkarev et al., 2012). HCT-15 colon cancer cell line, PC-3 prostate cancer cell line,
398 M.H. Semreen et al. / Saudi Pharmaceutical Journal 26 (2018) 396–409

Fig. 2. Structures of Gageosatins A–C.

NCI-H23 lung cancer cell line, NUGC-3 stomach cancer cell line, and
ACHN renal cancer cell line, and their GI50 values ranged from 4.6 to
19.6 mg/ml. They were also tested for antifungal and bacterial activ-
ities against R. solani, C. acutatum, and B. cinera fungi, in addition to
S. aureus, B. subtilis, S. typhi, and P. aeruginosa with MIC ranging from
4 to 64 mg/ml. It was reported that a combination between Gageo-
statins A and B showed greater antibacterial activity than individu-
als. The three compounds differ in molecular weight and structure,
but they all possess the same amino acid sequence (ELLVDLL)
(Tareq et al., 2014a).
Acosta et al. (2013) were capable of identifying three AMPs from
piscidin that were isolated from the Teloest fish, tilapia gills called
(Oreochromis niloticus). These peptides had the names and molecular
weights of oreochromicins (Oreoch-1, 2524.40 Da; Oreoch-2,
2981.60 Da; and Oreoch-3, 3654.19 Da), the three AMPs are com-
posed of a signal peptide which is highly cationic in nature with uni-
form net charges of 5, 7, and 10, and constituted of 23, 25, and 32
amino acid residues, respectively. The three peptides displayed Fig. 3. 3D structure of cod defb (Acosta et al., 2014).
activity against a wide range of bacteria and fungi, specifically
Oreoch-1 (FIHHIIGGLFSVGKHIHGLIHGH) that showed activity
against Gram-positive bacteria like S. aureus (MIC = 5 mM) and as adjuvant candidates for vaccine development was investigated by
B. subtilis (MIC = 3 mM), and Gram-negative bacteria like P. aeruginosa their co-administration to fish and mice infected with inactivated bac-
(MIC = 35 mM) and E. coli (MIC = 6.7 mM), as well as antifungal activity teria and virus that served as the subunit antigen. The results of this
against C. albicans (MIC = 20 mM) (Mygind et al., 2005). While in vivo study indicated that the three oreoch compounds were capable
Oreoch-2 (FIHHIIGGLFSAGKAIHRLIRRRRR) showed similar potency of inducing a hormonal and cellular responses in the infected species
to Oreoch-1 against S. aureus (MIC = 5 mM), B. subtilis (MIC = 1.7 mM), as well. The study described the powerful impact of the combination
P. aeruginosa (MIC = 6.7 mM), E. coli (MIC = 5 mM), E. tarda (MIC = 20 m of Oreoch-2 along with Oreoch-3 as this combination resulted in a sig-
M), and C. albicans (MIC = 26.7 mM). Lastly, the third AMPs Oreoch-3 nificant increase in the produced antibody amounts. Hence, according
(IWDAIFHGAKHFLHRLVNPGGKDAVKDVQQKQ) showed greater anti- to the study results, oreoch compounds are to be considered as strong
fungal activity compared to antibacterial, where it was active mainly and successful candidates for molecular adjuvants in vaccination
against C. albicans (MIC = 40 mM) but very weak against B. subtilis (MIC (Acosta et al., 2014).
= 106 mM), E. tarda (MIC = 160 mM), and Vibrio sp. (MIC = 106 mM). The b-defensins are a large family of broad-spectrum AMPs.
ability of oreoch compounds to induce an immune response and serve Cod b-defensin [defb] [WSCPTLSGVCRKVCLPTEMFFGPLGCG
 M.H. Semreen et al. / Saudi Pharmaceutical Journal 26 (2018) 396–409 399

KEFQCCVSHFF] is a novel antimicrobial peptide that belongs to the of the potent anti-infective ability of both As-CATH4 and As-
Defenisins family, this family of compounds has a diversity of func- CATH5 in crab’s aquatic organisms (Guoa et al., 2017).
tions and protective roles. Defb was identified from the Atlantic cod A cathelicidin from the sea snake Hydrophis cyanocinctus was
Gadusmorhua. The structure is enriched with six cysteine residues identified as Hc-CATH having the amino acid sequence KFFKRLLK
that make three disulfide bridges, which are accommodated in the SVRRAVKKFRKKPRLIGLSTLL. It demonstrated potent and broad-
compound’s tertiary structure composed of one a helix and three spectrum antimicrobial activity through disruption of the cell
ß sheets (Fig. 3). The compound has a molecular weight of 4490 membrane and lysis of the bacterial cell. Hc-CATH displayed pow-
Da, and a uniform net charge of +1. Defb shows activity against erful activity against human pathogenic microorganisms, with
Gram-positive M. lutes ATCC 4698 (MIC = 25–50 mM) and P. citreus MICs ranging from 0.16 mM (toward Shigella dysenteriae) to 20.67
NCIMB 1493 (MIC = 0.4–0.8 mM). However, the in vivo study sug- mM (toward Klebsiella 8). Keeping into consideration that the a
gested potential activity for this compound against Gram-negative helix conformation as well as the positive charge of the peptide
bacteria as this gene expression was highly upregulated in the head are essential for the antimicrobial activity. It is unlikely that the
kidney of the challenged atlantic cod with Vibrio anguillarum. In bacteria would develop resistance to this peptide because of its
addition, the Defb showed phagocytic activity on the prepared head rapid bactericidal effect. In addition to that, Hc-CATH is reported
kidney leucocytes obtained from five Atlantic cods (Ruangsri et al., to possess anti-inflammatory effects, extreme stability in aqueous
2013). solutions and very low cytotoxicity toward tested mammalian
The Clam antimicrobial peptide V. philippinarum defensin cells. It was also shown that human serum proteins can degrade
(VpDef) (GFGCPEDEYECHNHCKNSVGCRGGYCDAGTLRQRCTCYGCN and bind to Hc-CATH. On the other hand, unlike many antimicro-
QKGRSIQE) possesses combined helix and beta structure, and four bial peptides, Hc-CATH’s antimicrobial activity is highly salt resis-
potential disulfide bonds. The recombinant VpDef (rVpDef) was tant implying great potency for application (Wei et al., 2015).
expressed in E. coli Origami (DE3) as a C-terminal His6-tagged fusion Li et al. (2014) were capable of identifying, characterizing, and
protein. VpDef transcripts were significantly induced in the hemo- purifying a new AMP from the hemolymph of Mytilud coruscus a
cytes post Vibrio anguillarum infection. rVpDef showed high activity mollusks species called mytichitin-CB (TVKCGMNGKMPCKHGA
against Gram-positive bacteria Micrococcus luteus (MIC = 6.25–12.5 FYTDTCDKNVFYRCVWGRPVKKHCGRGLVWNPRGFCDYA) with a
mM) and less activity against Gram-negative bacteria like Proteus molecular weight of 6621.55 Da. This molecule has some special
mirabilis (MIC = 50–100 mM) (Zhang et al., 2015). features that include the chitin-binding domain for the drug,
CATH-BRALE is a salmonoid cathelicidin that is expressed from where preformed studies have shown C-terminal chitin-binding
an ancient fish called Bracgymysttazlenok. This AMP belongs to the domain of human ChT allowed the drug from binding to chitin. It
Cathelicidins family which are considered to be an essential com- is constituted of 55 amino acid 6 of which are cysteines forming
ponent of the innate immune system that is capable of playing 3 disulfide linkages. This drug is specific against Gram-positive
antibacterial and immunomodulatory role. This compound is com- bacteria, and some fungi where it showed activity against
posed of 199 amino acids, rich in arginine and glycine giving the B. subtilis, S. aureus, S. luteus; and B. megaterium (MIC < 5 mM), fungi
compound an intense positive charge [uniform net charge +13]. C. albicans and M. albicans (MIC 6.2–25 mM).
CATH-BRALE is described to be composed of antiparallel b-sheets SM HEP1p and SM HEP2p are two hepcidin AMPs that are rich
protruded by a-helices. This compound exhibited greater potency in cysteines which make 4 disulfide bond needed for the mole-
against Gram-negative bacteria where it has shown to effectively cule’s tertiary structure. They are isolated from turbot called Scoph-
inhibit Gram negative fish bacterial pathogens, Aeromonas salmoni- thalmus maximus. SMHEP1 which is composed of 26 amino acids
cida and Aeromonas hydrophila with a low MIC value against both has a uniform net charge of 4 and its sequence is
pathogens (9.38 lM). It has also displayed some antifungal activity (QSHISLCRWCCNCCKANKGCGFCCKF) with a molecular weight of
against C. albicans ATCC 2002 (MIC = 2.3 mM) (Li et al., 2013). 2940 Da while SMHEP2 which is made up of 22 amino acid resi-
As-CATH4 (amino acid sequence: RRGLFKKLRRKIKKGFK dues has a uniform net charge of 3 and the following sequence
KIFKRLPPVGVGVSIPLAGRR) and As-CATH5 (amino acid sequence: (GMKCKFCCNCCNLNGCGVCCRF) and its molecular weight is
TRRKFWKKVLNGALKIAPFLLG) are two novel compounds that 2410 Da. When it comes to their antimicrobial activity, it was
belong to the cathelicidins family of AMPs. These compounds noted that against Gram-positive bacteria SEM HEP1p showed
impact on the immune system was tested by their administration greater potency, where it was active against both S. aureus (MIC
to the Chinese mitten crab. The injection of both compounds in the = 2 mM) and M. luteus (MIC = 1 mM). Unlike SEM HEP2p that
crab induced an increase in the activity of two enzymes, acid phos- showed much greater activity against Gram-negative bacteria,
phatase and alkaline phosphatase. Hence, this in vivo study where it was potent against the following Gram-negative E. tarda
demonstrates the role of these compounds as immunostimulants. (MIC = 1 mM) and V. anguillarum (MIC = 2 mM), and both com-
Additionally, this immunostimulatory effect had a positive impact pounds displayed antiviral activity. As for their mechanism of
on improving the anti-infective capacity of the drugs, as the bacte- action, it is most likely that they act as bactericidal by inducing cell
rial load in the two groups of infected crabs was significantly membrane destruction and causing severe permeability disrup-
reduced upon As-CATH4 and As-CATH5 administration. The bacte- tion. Despite the described activity for both compounds, the pre-
ricidal activity was further supported by the in vitro results where formed in vivo and in vitro studies confirm that SmHep2p was
both compounds were effective against the tested ten different superior to SmHep1p as antimicrobial agents. The preformed
bacterial strains. Among these ten strains, eight strains were in vitro studies showed that both compounds were successful in
known to be ampicillin-resistant pathogens, and yet the com- inhibiting bacterial growth in fish cells. However, the in vivo study
pounds proved efficacy in low concentrations against them. This done on the turbot given the two compounds showed an increase
highlights the potential unique application of As-CATH4 and As- in its bacterial and viral resistance (Zhang et al., 2014).
CATH 5 against drug resistant pathogens. The killing kinetics assay SA-hepcidin1 (QSHLSMCRYCCNCCRNNKGCGFCCKF) and SA-
revealed the feature of the rapid killing effect where it took less hepcidin2 (NPAGCRFCCGCCPNMIGCGVCCRF) are cationic hep-
than 20 min to have the colony-forming unit of the treated bacteria cidins from the spotted scat fish (Scatophagus argus). The antibac-
with As-CATH5 to be reduced and remain zero. When the bacteri- terial activity of both SA-hepcidin1 and SA-hepcidin2 were
cidal mechanism was investigated for these compounds, it showed similar against Gram-positive bacteria Staphylococcus aureus
their ability of targeting the cell membrane and increasing the (MIC = 50 mM) and Gram-negative bacteria Vibrio anguillarum
permeability and cell disruption. These results provide evidence (MIC = 50 mM) and Vibrio alginolyticus (MIC = 50 mM). Moreover,
400 M.H. Semreen et al. / Saudi Pharmaceutical Journal 26 (2018) 396–409

SA-hepcidin1 showed strong antibacterial activity against Gram- tiae819, E. faecalis BCRC 10066, and S. agalactiae BCRC 10787 and
negative bacteria Vibrio fluvialis (MIC = 25 mM) and Escherichia coli Gram-negative V. vulnificus 204, V. alginolyticus. TP4 which is O.
(MIC = 50 mM), whereas SAhepcidin2 did not. In addition to the niloticus moronecidin-like peptide had a minimal inhibitory con-
antibacterial effect, SA-hepcidin2 showed antiviral activity against centration range of 0.03–2 lg/ml against a variety of Gram-
enveloped and non-enveloped viruses, being most effective against positive including Acteria S. agalactiae 819, E. faecalis BCRC 10066,
MsReV. One possible mechanism of action as antiviral is causing and S. agalactiae BCRC 10787 and Gram-negative including V. vul-
virion collapse, thereby preventing viral attachment to host cells nificus 204, A. hydrophila BCRC 13018, V. alginolyticus, and P. aerug-
(Gui et al., 2016). inosa ATCC 19660. Also TP4 showed promising activity against H.
YFGPA (VKVGINGFGRIGRLVTRAAFHGKKVEVVAIND) AMP is pylori, and triple-negative breast cancer (Peng et al., 2012).
considered as a GAPDH related compound. GAPDH is the glycolytic In addition, the activities of TP3 and TP4 were examined in vivo,
enzyme glyceraldehyde-3-phosphate dehydrogenase that has mul- where the antimicrobial potencies of TP3 and TP4 were investi-
tiple essential intracellular functions, in addition to the newly dis- gated by the eradication of acute bacterial infection from hybrid
covered antimicrobial properties. YFGPA was obtained from the tilapia fish. Upon infection of the Tilepia fish with V. vulnificus,
yellowfin tuna, Thunnus albacares. Its molecular weight is 3400 the co-administration of TP3 and TP4 at a dose of 20 mg/fish for
Da. The antimicrobial spectrum was proven to cover Gram- each agent, resulted in a survival rate of 95.3% and 88.9%, respec-
positive bacteria such as Bacillus subtilis, Micrococcus luteus, and tively, seven days following the treatment. Moreover, this study
Streptococcus iniae with minimal effective concentrations (MECs) demonstrated that the pretreatment of the fish with TP3 and TP4
of 1.2–17.0 mg/mL, as well it showed activity against Gram- prior to infection would result in a survival rates of 28.9% and
negative bacteria like Aeromonas hydrophila, Escherichia coli D31, 37.8%, respectively, while injecting the fish with TP3 and TP4 30
and Vibrio parahaemolyticus (MECs = 3.1–12.0 mg/mL). The pre- min after infection gave 33.3% and 48.9% survival rates, respec-
formed killing kinetic study against B. subtilis, and E. coli D31 tively (Pan et al., 2017).
showed that YFGPA has a bacteriostatic activity rather than bacte- SpHyastatin protein from the Crab Scylla paramamosain displays
ricidal activity, as it acts through non-lytic pathway. The low cyto- a broad antimicrobial spectrum. Potent activities against Gram-
toxicity of YFGPA makes it a potential alternative therapeutic agent positive bacteria (Micrococcus luteus, Staphylococcus aureus,
for humans or a substitute to conventional antibiotics for manag- Corynebacterium glutamicum, Micrococcusluteus) and Gram-
ing fish diseases (Seo et al., 2014a). negative bacteria (Pseudomonas stutzeri, Pseudomonas fluorescens,
Piscidins are known to have good antimicrobial activity and are Aeromonashydrophila) with MIC values of 0.63–2.5 mM, as well as
important for innate host defense. Rock bream piscidin (Rbpisc) values of MBC lower than 10 mM were demonstrated. In an
(GEGFLGMLLHGVGHAIHGLIHGK) has a tertiary structure which in vivo study, Scylla paramamosain crab was infected with V. para-
includes amphipathic helix-loop-helix structure. This unique haemolyticus to compare whether suppression of SpHyastatin
structure of the peptide enables it to interact electrostatically with would affect the survival rates following infection with V. para-
the negatively-charged bacterial membrane inserting the haemolyticus. The results revealed that at 60 h, 13% of the control
hydrophobic region into the lipid bilayer and puncturing the bac- group survived while none of the SpHyastatin-suppressed crabs
terial membrane, which is a crucial step to the antimicrobial activ- survived. It was proposed that this compound was capable of erad-
ity. In vitro, it showed very strong antibacterial activity against S. icating the bacterial infection via an immune reaction. Further-
iniae, V. harveyi and V. ordalii with MICs lower than 0.9 mM, and more, this in vivo study revealed a unique property about
against V. ordalii (7.8–15.6 mM). Rbpisc also showed weak antimi- SpHyastatin, it has the highest transcription level among six other
crobial activity against E. coli, Vibrio alginolyticus and V. campbellii, tested AMPs on the infected crab, indicating the high potential of
as indicated by the MIC and IC50 values (1.9–3.9 and 125–250 mM, pathogen resistance to this compound (Shan et al., 2016).
respectively). It is known that in order to apply any antimicrobial Sphistin is a cationic, amphiphilic a-helical antimicrobial pep-
peptide as an antibiotic, it should have low toxicity or hemolytic tide with a uniform net charge of +9. The 38 amino acid sequence
activity, unfortunately the analysis done by Bae et al. (2016) of Sphistin peptide (MAGGKAGKDSGKAKAKAVSRSARAGLQFPV
revealed that the peptide exhibited significant hemolytic effect GRIHRHLK) was derived from the N terminus of the crab (Scylla
against fish erythrocytes at concentrations higher than 500 lM paramamosain) histone H2A. It exerts its antimicrobial function
which is the concentration that effectively inhibited E. tarda and through electrostatic attraction because of its cationic characteris-
V. vulnificus. However, Rbpisc did not exhibit cytotoxicity at the tics. Sphistin was effective against the growth of Gram-positive
effective concentration against S. iniae, V. alginlyticus, V. harveyi, bacteria (S. aureus, C. glutamicum, Bacillus subtilis, Micrococcus
and V. ordalii. lysodeikticus, and Micrococcus luteus) and Gram-negative bacteria
Peng et al. discovered five piscidin-like AMPs, two of which are (Shigella flexneri, Pseudomonas stutzeri, and Pseudomonas fluo-
having potent antimicrobial activity which are named TP3 (FIH- rescens) with MIC values lower than 1.5 mM as well MBC lower than
HIIGGLFSVGKHIHSLIHGH) and TP4 (FIHHIIGGLFSAGKAIHR- 12 mM. It was demonstrated that sphistin exerted its antimicrobial
LIRRRRR). These compounds were derived from Nile tilapia, activity via adsorption, followed by permeabilization and finally
Oreochromis niloticus. They share similar amphipathic a-helical damaging the bacterial cell membranes. Fortunately, sphistin did
structure and cationic nature that attribute in part to their activity. not display toxicity towards either mammal or crab normal cells
The selective toxicity and hemolytic activity of these two com- (Chen et al., 2015).
pounds were examined by comparing the toxicity against human Pt5e is a peptide derived from fish egg yolk protein phosvitin.
mammalian normal cells and Hela cells of cervical tumors. The pre- Its recombinant analogue (rPt5e) was expressed in E. coli Transetta
formed in vitro study conveyed that TP3 was selective to tumor (DE3) strain. It was purified by inverse transition cycling (ITC)
cells over normal cells. In contrast, TP4 showed no selectivity technique, and the yield was 2.39 mg from 100 ml culture. It has
between both the normal and tumor cells. In addition, the hemoly- shown the ability to kill clinical multidrug resistant bacteria;
tic studies showed that TP4 is capable of inducing hemolysis to E. coli 577 (MIC = 2.1 mM), E. coli 4457 (MIC = 2.1 mM), Klebsiella
human erythrocytes while TP3 exerted less capability of inducing pneumoniae 2182 (MIC = 2.1 mM), E. coli 140237 (MIC = 2.1 mM),
it. Both compounds showed antibacterial activity against both and Acinetobacter baumannii7225 (MIC = 1.4 mM) in a dose-
Gram-positive and Gram-negative bacteria where TP3 which is O. dependent manner. To confirm the interaction between Pt5e and
niloticus dicentracin-like peptide had a minimal inhibitory concen- the bacteria, the membrane proteins were extracted from the mul-
tration range of 0.6–20 mg/mL against Gram-positive S. agalac- tidrug resistant (MDR) bacteria and treated with Pt5e, then they
 M.H. Semreen et al. / Saudi Pharmaceutical Journal 26 (2018) 396–409 401

were subjected to Western blotting analysis. The extracted mem- the MIC of EeStrongylocin 2 was found to range from 0.78 to
brane proteins of the MDR bacteria that were treated with Pt5e 3.13 lM (Solstad et al., 2016).
reacted with anti-His tag mouse monoclonal antibody, on the other From the large yellow croaker (Larimichthys crocea) which is a
hand, the membrane proteins of the same bacteria treated with marine fish in China, Lc-NK-lysin was extracted with the amino
phosphate buffered saline (PBS) did not react, indicating that the acid sequence: MNSSSVLFVCILGACSVWTVHGRNLKVNDDDQEGAEL
extracted proteins of the MDR bacteria treated with Pt5e contained DISVEARKLPGLCWVCKWSLNKVKKLLGRNTTAESVKEKLMRVCNEIGL
recombinant Pt5e. These findings suggested that Pt5e interacted LKSLCKKFVKGHLGELIEELTTSDDVRTICVNLKACKPKELSELDFESDEDA
with the membranes of the MDR bacteria causing membrane per- HTEMNDLLFE. Lc-NK-lysin mature peptide was divided into Lc-NK-
meabilization, depolarization, and increased the intracellular reac- lysin-1 and Lc-NK-lysin-2, and both of these two peptides showed
tive oxygen species, leading to bacterial cell death (Li et al., 2016). antibacterial activities. The Lc-NK-lysin-1 peptide exerted activity
From the fish orange-spotted grouper (Epinephelu scoioides), that could inhibit and kill S. aureus (MIC = 12–24 mM) and V. har-
ecPis-4 (FFRHIKSFWKGAKAIFRGARQG) was identified as having veyi (MIC = 12–24 mM). In addition, it could inhibit but could not
strong antibacterial activities, in addition to the two others; kill B. subtilis (MIC = 24–48 mM) and E. coli (MIC = 12–24 mM). In
ecPis-2 and ecPis-3. The three piscidins were synthesized in order contrast, even the highest concentration of Lc-NK-lysin-1 peptide
to determine their biological activity; they demonstrated antibac- could not affect V. parahaemolyticus, A. hydrophila, and P. damselae.
terial activities against fish pathogen V. parahaemolyticus, and For the Lc-NK-lysin-2 peptide, it exerted activities against S. aureus
human pathogen E. coli and S. aureus. MBCs were lower than 5.0 (MIC = 12–24 mM) and E. coli (MIC = 24–48 mM) (Zhou et al., 2016).
mmol/l for EcPis-2 and ecpis-4. However ecPis-3 MBCs were 5.0 WB Piscidin 5 (LIGSLFRGAKAIFRGARQGWRSHKAVSRYRAR
mmol/l against V. parahaemolyticus, 10 mmol/l against E. coli, and YVRRPVIYYHRVYP) is a host defense peptide found in the white bass
20 mmol/l against S. aureus (Zhuang et al., 2017). Morone chrysops. It was chemically synthesized and its antibacterial
MoroPC-NH2 (FFGHLFRGIINVGKHIHGLLSG-NH2) is synthetic, activity was tested. WB Piscidin 5 exhibited activity against E. fae-
amidated moronecidin-like peptides from the Antarctic Fish calis (MIC = 4.52 mM), S. aureus (MIC = 4.52 mM), Shigella flexneri (M
Parachaenichthyscharcoti. It showed strong activity against Gram- IC = 1.13–2.26 mM), and E. coli (MIC = 1.13 mM) (Salger et al., 2016).
negative Shigellasonnei, Psychrobacter sp., and E. coli DH5a (MICs Lysozyme from the seahorse Hippocampus abdominalis can cat-
< 12.5 lM). In addition, Gram-positive bacteria; Enterococcus fae- alyze the hydrolysis of the bacterial cell wall, making it a good
calis, Streptococcus pyogenes, Staphylococcus aureus, and Listeria- antibacterial agent in the innate immune system. ShLysG is a
monocytogenes are sensitive to the peptide below 25 lM. On the polypeptide obtained from H. abdominalis containing 184 amino
other hand, moroNC-NH2 (FFWHHIGHALDAAKRVHGMLSG-NH2) acids (MGYGDIMKVDTSGASMKTAGQDRLTYAGVAASNTMAQTDLG
is another synthetic, amidated moronecidin-like peptides obtained RMNNYKAIIQRVGGKKDVDPAIIAGIISRESRAGNVLVNGWGDNGNA
from the Antarctic Fish Notothenia coriiceps; having lower antibac- WGLMQVDKRYHTPQGGWNSEEHLSQGTDIISFIKQVQGKFPSWTAEQ
terial activity and a narrower spectrum. This might be a result from QLKGGIAAYNIGLGGVQTYERMDVGTTGDDYSSDVVARAQWYKSQG
its lower hydrophobicity. Salts can decrease the activity of antimi- GF). It has a molecular mass of 20,000 Da. The conserved catalytic
crobial peptides since they disrupt the electrostatic interactions bacterial soluble lytic transglycosylase domain in ShLysG contains
needed for forming pores in the microbial membrane. The activity three catalytic residues and seven N-acetyl-D-glucosamine binding
of moro-NH2 was affected by salt concentration as evidenced by sites. This domain is crucial for the hydrolysis of the b-1,4-
the increase in the MIC in the presence of 500 mM NaCl or 5 mM glycosidic bonds between the N-acetylmuramic acid and
CaCl2. Besides, it was concluded that it is difficult to consider N-acetylglucosamine of peptidoglycan in the bacterial cell wall.
moroNC-NH2 for clinical use since it has a narrow spectrum of X-ray crystal structure reported that Glu73 and two aspartic acid
antibacterial activity and high salt sensitivity. Upon examining residues (Asp90 and Asp101) are also directly associated with the
the effect of the temperature on the antimicrobial peptides catalytic reaction. rShLysG presented antimicrobial activity
(moro-NH2, moroNC-NH2, and moroPC-NH2), none of the temper- towards the five bacterial strains; V. salmonicida, V. parahemolyti-
atures tested (15 °C, 20 °C, 30 °C, and 37 °C) affected the activities cus, L. monocytogenes, S. iniae, and V. anguillarum (Ko et al., 2016).
of the peptides (Shin et al., 2017). A set of Histone H2A fragments were isolated from the Russian
PaLEAP-2 (MTPLWRVMGNKPFGAYCQDHVECSTGICKGGHCITSQ sturgeon (Acipenser gueldenstaedtii). They were called acipensins1,
PIKS) is an antimicrobial peptide from the teleost fish Plecoglossus 2, 6 (Ac1, Ac2, Ac6). The peptides Ac1 and Ac2 displayed potent
altivelis, after being chemically synthesized; it exhibited selective antimicrobial activity towards Gram-negative and Gram-positive
antimicrobial activity in vitro against various bacteria. Its potencies bacteria, while Ac6 was only effective against Gram-negative bac-
towards E. tarda and V. anguillarum are the highest (6.25 mg/ml). teria. Ac1 (SGRGKTGGKARAKAKTRSSRAGLQFPVGRVHRLLRKG
While the MIC value against Escherichia coli DH5a is 50 mg/ml. Also, NYAQRVGAGAPVY) presented MIC = 0.7 mM against E. coli ML35p,
P. putida, V. alginolyticus, and V. vulnificus were sensitive to PaLEAP- MIC = 1.1 mM against Listeria monocytogenes EGD, and MIC = 0.9 m
2 (MIC = 100 mg/ml). The mode of action of LEAP-2 was suggested M against methicillin-resistant Staphylococcus aureus (MRSA) ATCC
as hydrolyzing the DNA as a means to kill the bacteria. In addition, 33591. Meanwhile, Ac2 (SGRGKTGGKARAKAKTRSSRAGLQFPVGRV
in vivo studies revealed that at high concentrations of PaLEAP-2 HRLLR) presented MIC of 0.3 mM against E. coli, MIC = 1 mM against
the mortality caused by V. anguillarum infection was significantly L. monocytogenes, and MIC = 0.6 mM against MRSA. Finally, Ac6 (ILE-
decreased; this is promising since the main causative agent for LAGNAARDNKKTRIIPRHLQL) had activity only against E. coli with
Vibriosis, which is a prevalent disease in ayu culture in China, is MIC = 2.5 mM. All three peptides were devoid of hemolytic activity
V. anguillarum (Li et al., 2015). against human erythrocytes at concentrations of 1–40 lM and at
EeCentrocin 1 (GWWRRTVDKVRNAGRKVAGFASKACGALGH), concentrations 1–20 mM they did not exert toxic effects on the cells
EeCentrocin 2 (WGHKLRSSWNKVKHAVKKGAGYASGACRVLGH) (Shamova et al., 2014).
and EeStrongylocin 2 (WNPFKKIAHRHCYPKNECITTNGKKTCK SJGAP is another AMP (VKVGINGFGRIGRLVTRAAFHGKKVEI
DYSCCQIVLFGKKTRSACTVVAQ) are peptides isolated from the edi- VAIND) obtained from skin extract of skipjack tuna (Katsuwonus
ble sea urchin Echinus esculentus. EeCentrocin 1 is potent against pelamis). It exhibited potent antimicrobial activity against
the Gram-positive bacteria; C. glutamicum (MIC = 0.78 lM) and S. Gram-positive bacteria, such as B. subtilis, M. luteus, S. aureus, and
aureus (MIC = 0.78 lM), and against the Gram-negative bacteria, S. iniae (MEC = 1.2–17.0 mg/mL), and Gram-negative bacteria, such
E. coli (MIC = 0.1 lM) and P. aeruginosa (MIC = 0.78 lM), whereas as A. hydrophila, E. coli D31, and V. parahaemolyticus (MEC = 3.1–1
402 M.H. Semreen et al. / Saudi Pharmaceutical Journal 26 (2018) 396–409

2.0 mg/mL). SJGAP consists of one a helix and two parallel b- properties, varieties of analogues were prepared including, N2, N3,
strands, and it forms an amphipathic structure. Also, it acts N4, N5, N6 and N7 by structural modification of the natural peptide
through bacteriostatic process rather than bactericidal one since N1 through changing the number and locations of the disulfide
it displays a small degree of leakage ability (Seo et al., 2014b). bonds. The NMR spectral analysis identified four different classes
LEAP-2 is an important molecule of miiuy croaker’s innate of peptides designed based on structural determinants: (I) Rocket
immune system as it provides resistance against bacterial infec- analogues with two disulfide bonds (N2: Gly1, 12 ? Ala; N3: Trp4,
tions. It was found that LEAP-2 (MTPLWRIMNSKPFGAYCQN Asn5 ? Ala; N4: Trp0). (II) Kite analogue with a Cys7-Cys16 disul-
NYECSTGLCRAGHCSTSHRATSETVNY) has a molecular mass of fide bond (N6: Cys3,20 ? Ala). (III) Bullet analogue with a Cys3-
5000 Da and its instability index is 34.74, which means that the Cys20 disulfide bond (N7: Cys7,16 ? Ala). (IV) Other disulfide
polypeptide is a stable protein. It was effective in controlling A. bond-free linear analogues (N5: DCys3,7,16,20; N8: Cys3,7,16,20
hydrophila showing bacteriostatic diameter of 10 mm (Liu et al., ? Ala) (Harwing et al., 1996; Yang et al., 2017). The four classes dis-
2014). played in vitro activity against a wide range of microorganisms
Hemocyanins are multifunctional proteins that can be found in including Gram-negative and Gram-positive bacteria, and fungi.
invertebrates including molluscs. Zhuang et al. (2015) identified The Rocket N2 analogue, with two disulfide bonds, showed the
haliotisin, a hemocyanin-derived antimicrobial peptide from the strongest antimicrobial activity against Gram-negative bacteria
mollusk Haliotis tuberculate. Haliotisin peptide 3-4-5 (DTFDYKKF- with MIC values ranging from 0.25 to 1 mg/ml against E. coli, Sal-
GYRYDSLELEGRS ISRIDELIQQRQEKDRTFAGFLLKGFGTSAS) exhib- monella, and Pseudomonas strains and lower cytotoxicity compared
ited antibacterial activities. Peptide 3 displayed MIC = 0.3–1 mM to other analogues (Wang et al., 2017). N2 and N6 analogues were
against B. subtilis, while peptide 4 displayed MIC = 1.6–2.6 mM less cytotoxic against RAW 264.7 macrophages, compared with
against E. carotovor, in addition to peptide 5 which showed N1. Both N2 and N6 analogues induced cell cycle arrest in I- and R-
1.2–1.5 mM against E. carotovar. phases, respectively, in E. coli and S. enteritidis. In E. coli and in S.
The novel 55 amino acid peptide cgMolluscidin (AATAKKGAKKA enteritidis, both peptides inhibited DNA/RNA/cell wall synthesis by
DAPAKPKKATKPKSPKKAAKKAGAKKGVKRAGKKGAKKTTKAKK) with 18.7–43.8% and 5.7–61.8%, respectively. They also modified the
a molecular weight of 5500 Da, extracted from the pacific oyster morphology of E. coli cells to become collapsed and filamentous after
Crassostrea giga, exerted potent antimicrobial activity against both treatment with the two peptides. The survival rate of peritonitis-
Gram-positive bacteria including B. subtilis, M. luteus, and S. aureus and endotoxemia-induced mice was prolonged, the serum levels
(MEC = 1.3–31.3 mg/mL), and Gram-negative bacteria including of interleukin-6 (IL-6), IL-1b, and tumor necrosis factor a (TNF-a)
E. coli, S. enterica, and V. parahaemolyticus (MEC = 0.4–2.3 mg/mL) decreased following doses ranging from 2.5 to 7.5 mg/kg body
(Seo et al., 2013a,b). weight. These peptides prevented lipopolysaccharide (LPS)-
PdBD-2 (YDTGIQGWTCGSRGLCRKHCYAQEHTVGYHGCPRRYRC induced lung injury in mice (Harwing et al., 1996; Yang et al., 2017).
CALRF) was identified from the Chinese loach fish, Paramisgurnus
dabryanus and it significantly inhibited the growth of the Gram-
negative bacteria A. hydrophila and the Gram-positive B. subtilis 3. Antimycobacterial marine peptides
(Chen et al., 2013a).
From the pacific oyster Crassostrea gigas, the 74 amino acid The development of resistance to both first and second line
cgUbiquitin (MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQ anti-TB medications has decreased the effective management of
QRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLR) was identified, having TB. Thereby, it is essential to increase the efforts and focus on
a molecular weight of 8471 Da. It is composed of three a-helices the investigation and development of new anti-TB drugs. Accord-
and four b-strands separated by 7 loop regions. It is active against ingly, research was directed to the naturally occurring compounds
both Gram-positive and negative bacteria including S. iniae (MEC = such as peptides.
7.8 mg/mL) and V. parahemolyticus (MEC = 9.8 mg/mL) without caus- Lobophorin G, Lobophorin A, and Lobophorin B (Fig. 4) are
ing hemolysis to human red blood cells up to 100 mg/mL. Moreover, isolated from an Actinomycete strain. The molecular weights of
according to the kinetics of killing and membrane permeabilization Lobophorin G, A, and B are 1225.75 Da, 1161.70 Da, and 1191.68
studies, it was illustrated that cgUbiquitin was not membrane per- Da, respectively. As for the biological activity, the three compounds
meable and acted through a bacteriostatic process (Seo et al., have showed a moderate activity against M. tuberculosis yet a
2013a,b). strong activity against Mycobacterium bovis BCG. Lobophorin G
Chionodracine (FFGHLYRGITSVVKHVHGLLSG), isolated from the and lobophorin A have produced the same MIC values against M.
icefish species Chionodracohamatus, exhibited significant effect bovis BCG with (MIC = 1.56 mg/ml) and the same MIC value against
against Antarctic psychrophilic bacteria strains Psychrobacter sp. M. tuberculosis which is 32 mg/ml. However, lobophorin B has a
TAD1 (MIC = 10 mM) and TA144 (MIC = 15 mM at 15 °C), the Gram- lower MIC value that is almost half of that produced by lobophorin
positive B. cereus (MIC = 5 mM at 25 °C), and the Gram-negative G and lobophorin A, which is 0.78 mg/mL against M. bovis BCG and
E. coli (MIC = 5 mM at 25 °C). However, when the activity of the 16 mg/ml against M. tuberculosis, indicating a higher potency of
peptide was tested at 37 °C against E. coli and B. cereus the MIC lobophorin B against the two microorganisms when compared to
levels increased to 20 mM and 10 mM, respectively. Buonocore lobophorin G and lobophorin A (Chen et al., 2013b).
et al. suggested that this could be an indication that chionodracine Microcystin-LR (D-Leu1) MC-LR obtained from Microcystis
is adapted to low temperatures or that there was a conformational aeruginosa, are cyclic heptapeptides that are made up of seven
change in the bacterial membrane due to the lower temperature, amino acids, two of which are protein amino acids which are
leading to higher susceptibility to the peptide. A test was done essential for the discrimination of the structural variants of
in vitro on human erythrocytes and no significant lysis occurred microcystins, while the remaining five are non-protein amino acids
with the use of Chionodracine until the concentration reached which are common between the variants. An example of a
50 mM (Buonocore et al., 2012). compound that belongs to the microcystins is microcystin-LR
The NZ17074 (N1) is a marine peptides derived from the marine (D-Leu1) MC-LR. It contains a leucine and an arginine residue in
invertebrate lugworm Arenicola marina. It is characterized by disul- its structure, with a leucine residue that is present at position 2
fide bonds. It was proven to show a potent antibacterial activity (Fig. 5). The amino acid residues present at that position may vary
against Gram-negative bacteria, antifungal and cytotoxicity. How- in other microcystins. The mechanism of action involves the inhi-
ever, to reduce its cytotoxicity and to improve its physicochemical bition of the serine/threonine phosphatases 1 and 2A which are
 M.H. Semreen et al. / Saudi Pharmaceutical Journal 26 (2018) 396–409 403

Fig. 4. Structures of Lobophorins G, A, and B, antimycobacterial peptides.

Theonellamide G was reported to have strong antifungal activity

and cytotoxic activity. The antifungal activity was measured
against two strains of Candida albicans, the wild type and ampho-
tericin B-resistant, with MIC values of 4.49 and 2.0 lM, respec-
tively. Furthermore, theonellamide G cytotoxic activity was
measured against the human colon adenocarcinoma cell line
(HCT-16) with IC₅₀ of 6.0 lM (Youssef et al., 2014).
From a deep-sea sediment in Calyptogenacommunity located in
Sagami Bay of Japan an Aneurinibacillus sp. YR247 was isolated and
tested for antimicrobial activity, resulting in an inhibitory activity
on Aspergillus brasiliensis with an inhibitory zone of 20.3 mm yet no
inhibitory activity on Candida albicans. Upon the antifungal activity
findings, the crude extract of YR247 was purified using silica gel
chromatography, and the purified compound had an average
molecular weight of 1167.9 Da which was identified via E.I-MS/
Fig. 5. General structure of Microcystin-LR (D-Leu1) MC-LR with leucine (L) in the MS. Furthermore, the effects of temperature and pH on antifungal
amino acid position 2 and arginine (R) in the amino acid position 4 and a leucine in activity were studied which resulted that the compound is stable
the amino acid position 1.
at 4–70 °C and pH 2.0–12.0, respectively (Kurata et al., 2017).
responsible for protein phosphorylation, this will result in Based on previous studies, which report findings of bicyclic
cytoskeletal damage, liver necrosis, and hemorrhage in the liver dodecapeptidestheonellamide (TNMs) A-E that butanol extract of
that is related to the cytotoxic as well as tumor promoting activi- marine sponge Theonella species showed antifungal and cytotoxic
ties of microcystins. As for the antimycobacterial activity, activity (Matsunaga and Fusetani, 1995). The structure of
microcystin-LR (D-Leu1) MC-LR has produced an MIC of 13.2 mM theonellamide-A is illustrated in Fig. 7. Theonellamides bind
against both the susceptible and rifampin-resistant M. tuberculosis specifically to 3-b-hydroxysterols, resulting in 1,3-b-d-glucan
strains and 26.5 mM against isoniazid-resistant M. tuberculosis overproduction and membrane damage in yeasts. In this study,
strains, indicating that it is a promising candidate for developing they specifically examined (TNM-A) membrane action, that was
new antimycobacterial drug (Ramos et al., 2015). assessed by 31P nuclear magnetic resonance (NMR) and confocal
microscopy, where they were able to conclude in combination with
earlier studies, that TNM-A binding to the membrane is facilitated
4. Antifungal marine peptides by the direct interaction of TNM-A with sterol found on the mem-
brane surface, consequently the accumulated TNM-A resulted in
A crude extract of Red Sea sponge Theonella swinhoei located in disruption of the membrane integrity and distortion in the mem-
Hurghada, Egypt, in the Red Sea coast, was subjected to multiple brane morphology (Espiritu et al., 2013; Espiritu et al., 2016).
chromatographic separations and a final HPLC purification, where Mohangamides A and B were isolated from marine Streptomyces
theonellamide G a bicyclic glycopeptide was determined (Fig. 6). sp. found in seashore mud located in Busan, Korea. Upon multiple
404 M.H. Semreen et al. / Saudi Pharmaceutical Journal 26 (2018) 396–409

Fig. 6. Chemical structure of Theonellamide G, antifungal peptide.

Fig. 7. Structure of Theonellamide A.

 M.H. Semreen et al. / Saudi Pharmaceutical Journal 26 (2018) 396–409 405

Fig. 8. Structures of Mohangamides A and B.

chromatographic and spectroscopic studies mohangamides struc- tions. In silico studies showed Cm-p5 binding to phosphatidylser-
tures were identified as novel structures, because it contained a ine bilayer, and isothermal titration calorimetry showed Cm-p5
unique dihydropyridine acyl chain and a dilactone-tethered pseu- having different affinities, where it possessed the highest affinity
dodimeric peptides (Fig. 8). Mohangamide A activity was tested to phospholipids of fungal membranes, intermediate affinity to
against C. albicans where it exhibited a strong inhibitory activity mammalian membrane phospholipid, lowest affinity to ergosterol,
against isocitratelyase with an IC50 of 4.4 lM, while Mohangamide and no affinity to chitin, respectively. Furthermore, in mice with
B with IC50 = 20.5 lM (Bae et al., 2015). candidiasis, Cm-p5 was administered i.p., but failed to control
From earlier studies, the researchers isolated Cm-p1 from a the fungal kidney burden.
coastal snail C. muricatus, which possessed antifungal activity. The heptacyclopeptide Stylissamide G (Fig. 9) was isolated from
Whilst in Lopez-Abarrategui et al. (2015) study, which described the Bahamian marine sponge Stylissa caribica located in the Carib-
the preparation of new Cm-p1 derivatives by adding 2 more resi- bean Sea. In the study performed by Dahiya et al., they were able to
dues to the C-terminus of Cm-p1 aiming at increasing the antifun- synthesize stylissamide G. Quantitative analysis were used to con-
gal activity. This addition gave rise to three new derivatives, and firm the structure of the synthesized stylissamide G, which was
out of the three Cm-p5 (SRSELIVHQRLF) seemed the most promis- evaluated against different fungal strains, and it exhibited antifun-
ing. Cm-p5 had a MIC value of 10 mg/ml; EC50 of 1.146 mg/ml gal activity at a concentration of 6 lg/ml, against pathogenic C.
against C. albicans, hence increased fungistatic activity compared albicans and dermatophytes Trichophyton mentagrophytes with an
to the parent peptide. Cm-p5 characterized by circular dichroism inhibitory zone of 22 mm and Microsporum audouinii with an inhi-
and nuclear magnetic resonance revealed an a-helical structure bitory zone of 23 mm. In addition, the antifungal activity might be
in lipophilic conditions and random coil folding in aqueous condi- linked to the inhibition of glucan/cell wall chitin/sphingolipids
synthesis. Stylissamide G can be delivered intravenously, subcuta-
neously, transdermally, or intranasaly to avoid possible degrada-
tion and limited absorption in the gastrointestinal tract (GIT) and
hepatic first-pass metabolism. Although oral delivery is challeng-
ing, structural modification such as cyclization provides resistance
to proteolytic degradation and has higher than expected absorp-
tion after oral administration in comparison to the linear counter-
parts (Dahiya et al., 2016).
Gageopeptides A D (Fig. 10) are four lipopeptides that were
obtained from marine-derived bacterium B. subtilis. They showed
antifungal activity with MIC values of 0.02–0.06 lM against Rhi-
zoctonia solani, Botrytis cinerea, and Colletotrichum acutatum that
are considered pathogenic fungi. In addition, Gageopeptides A–D
showed no cytotoxicity when tested on cancer cell line (Tareq
et al., 2014b).

5. Antiviral marine peptide

Marine antiviral peptides are unique natural antimicrobials, due

Fig. 9. Structure of Stylissamide G. to the presence of bioactive metabolites. These bioactive
406 M.H. Semreen et al. / Saudi Pharmaceutical Journal 26 (2018) 396–409

Fig. 10. Structures of Gageopeptides A-D.

metabolites come from different sources like sponges, fungi, and

fish. The bioactive peptides are either cyclic or linear peptides con-
taining atypical amino acids. They inhibit viral infection through
different mechanisms: (i) inhibition of virus attachment and entry;
(ii) inhibition of virus penetration; (iii) inhibition of nucleic acid
synthesis; (iv) inhibition of protein synthesis; (v) inhibition of
virus release (Sadorn et al., 2016). Among the marine antiviral
agents, the following agents were reported; Asperterrestide A,
EcDefensin, and Aspergillipeptide.
Asperterrestide A (Fig. 11) is a cyclic tetrapeptide, containing 3-
OH-N-CH3-Ph. residue, was isolated from the fungus Aspergillus
terreus SCSG AF0162. It showed an inhibitory effect against the
influenza strain A/WSN/33 H1N1 (an M2-resistant strain) and
strain A/Hong Kong/8/68 H3N2 (an M2-sensitive strain) with IC50
values of 15 and 8.1 mM, respectively (He et al., 2013; Kang et al.,
2015; Moghadamtousi et al., 2015; Sadorn et al., 2016;
Fig. 11. Structure of Asperterrestide A. Abdelmohsen et al., 2017).
 M.H. Semreen et al. / Saudi Pharmaceutical Journal 26 (2018) 396–409 407

Fig. 12. Structures of Aspergillipeptides.

EcDefensin possesses dual antiviral activity, inhibiting the slower and cytoplasmic infiltration was in one or two cell posi-
infection and replication of SGIV (an enveloped DNA virus of Singa- tions. Lastly at the lowest concentration (6 lM), no cell rupture
pore grouper iridovirus) and VNNV non-enveloped RNA virus of was seen but it was able to inhibit most trophonts swimming
viral nervous necrosis virus. It comes from marine organisms called and unusual morphological changes with minimum cytoplasmic
Epinephelus coioides. In vivo, EcDefensin was remarkably up- infiltration were observed (Niu et al., 2013).
regulated in both spleen and liver tissues in presence of the patho- EcPis-2, EcPis-3 and EcPis-4 are three putative piscidin par-
gens, including LPS, SGIV and polyI:C (a synthetic dsRNA). When alogues taken from orange-spotted grouper (Epinephelus coioides).
Ec-defenisn was used in concentrations less than 400 mg/ml, it They exhibited different activities against the theronts of C. irritans.
did not show cytotoxic effects on GS or EAGB cells. Regarding the When the theronts were exposed to these piscidin, they became
antiviral mechanism of this peptide, it exerts direct effect on viri- spherical, their motility decreased, and their membrane was rup-
ons in addition to some activity on target cell and both the innate tured. EcPis-3S exhibited the most potent activity against the
and adaptive immunity. Fortunately, the majority of microbial infective stage of C. irritanstheronts, where by using 5 mmol/l
pathogens have not developed resistance to defensins as antimi- ecPis-3S at 5 min post-treatment over 90% of the theronts were
crobial compounds (Cheung et al., 2014; Ma et al., 2017). rapidly disintegrated and lysed. About 30 to 50% of theronts when
Aspergillipeptides (1–2) (Fig. 12), are new cyclic pentapeptide 10 mmol/L were used of ecPis-2S, -2L, ecPis-3L, and ecPis-4S, -4L at
(compound 1) and linear peptide (compound 2). They were iso- 2 h post-treatment, were disintegrated and lysed and the rest
lated from fungus Aspergillus sp. SCSIO 41501. Compounds 1 and theronts were less motile. In vivo, the peptide FFFHIVKGLFHAGR-
2 showed antiviral activity against Herpes simplex virus type 1 MIHGLV was identified with 99% confidence by HPLC and
(HSV-1) with IC50 values of 9.5 and 19.8 mM, respectively. In addi- ESI-LCMS analysis, demonstrating high possibility that the short
tion compound 1 also had antiviral activity against acyclovir- N-terminal fragment of ecPis-2, ecPis-2S, exists as a mature
resistant clinical isolates of HSV-1 (Cheung et al., 2015). peptide of ecPis-2 in orange-spotted grouper (Zhuang et al., 2017).
Compounds 2,3,4 S Furthermore, two piscidins isolated from
6. Anitprotozoal marine peptides the fish Moronechrysops were identified to have activity against
the parasite Tetrahymena pyriformis. White bass piscidin 6 (LFGS
Pc-pis is a cationic AMP isolated from Pseudosciaena crocea. VKAWFKGAKKGFQDYRYQKDMAKMNKRYGPNWQQRGGQEPPADA
Quantitative PCR analysis revealed that the overexpression of Pc- QANDQPP) showed PCmin<0.25 mM and PC100 of 0.99. While (WB)
pis in the fish vital organs could be regulated during cryptocaryon Piscidin 5 (LIGSLFRGAKAIFRGARQGWRSHKAVSRYRARYVRRP
irritans infection and post C. irritans falling off, highlighting the role VIYYHRVYP) displayed PCmin of 0.56 mM and PC100 of 1.1 mM
of Pc-pis in immune defense against C. irritans and secondary bac- (Salger et al., 2016).
terial infections. The synthetic Pc-pis peptide was a new member
of the piscidin family were it exhibited a broad antimicrobial and
antiparasitic activities. Antiparasitic assays were done to trophont 7. Conclusion
of C. irritans that was rubbed off from the skin, pterygiophore, and
gill of heavily infected S. latus to see the change in morphology and Marine microorganisms are considered a rich source of antimi-
survival at different Pc-pis concentrations. Results revealed that at crobial agents. They can be used for different types of infections
low concentration of synthetic Pc-pis it was strongly active against like bacterial, viral, fungal and parasitic infections. The structure
C. irritanstrophonts. When trophonts were exposed to high concen- of marine AMPs can be utilized to develop novel compounds with
trations of Pc-pis, such as 24 or 48 lM, within minutes of exposure greater activity and stability, and to be used orally.
cytoplasmic infiltration from the trophonts which was dose- Because of multidrug resistance in bacterial, fungal, viral and
dependent was seen, at concentration of 48 lM the trophonts parasitic infections, there is demand for developing new classes
plasma membrane at several cell positions was completely and of antimicrobial agents to overcome this problem. So, AMPs are
immediately lysed, where at 24 lM Pc-pis lysing of parasites was considered a good solution for this problem.
408 M.H. Semreen et al. / Saudi Pharmaceutical Journal 26 (2018) 396–409

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