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Electronic Journal of Biotechnology
Universidad Católica de Valparaíso
ISSN: 0717-3458
Vol. 6, Num. 3, 2003, pp. 262-275
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Electronic Journal of Biotechnology, Vol. 6 No. 3, December 15, 2003
Antimicrobial peptides: A natural alternative to
chemical antibiotics and a potential for applied biotechnology
Sergio
H. Marshall*1, Gloria
Arenas2
1Laboratorio
de Genética e Inmunología Molecular,
Instituto de Biología,
Facultad de Ciencias Básicas y Matemáticas,
Pontificia Universidad Católica de Valparaíso,
Avenida Brasil 2950, Valparaíso, Chile,
Tel: 56 32 273373
Fax: 56 32 596703 E-mail: smarshal@ucv.cl
2Laboratorio
de Genética e Inmunología Molecular,
Instituto de Biología,
Facultad de Ciencias Básicas y Matemáticas,
Pontificia Universidad Católica de Valparaíso,
Avenida Brasil 2950, Valparaíso, Chile
Tel: 56 32 273205
Fax: 56 32 596703
E-mail: garenas@ucv.cl
*Corresponding author
Financial support: Project ICA4-2001-10023 (Immunaqua
project - European Community).
Received March 18, 2003 /
Accepted July 18, 2003
Code Number: ej03030
Abstract
A large group of low molecular weight natural compounds that
exhibit antimicrobial activity has been isolated from animals and plants during
the past two decades. Among them, cationic peptides are the most widespread.
Interestingly, the variety and diversity of these peptides seem to be much
wider than suspected. In fact, novel classes of peptides with varying chemical
propertiescontinue to be isolated from different vertebrate and invertebrate
species, as well as from bacteria. To the early characterized peptides, mostly
cationic in nature, anionic peptides, aromatic dipeptides, processed forms
of oxygen-binding proteins and processed forms of natural structural and functional
proteins can now be added, just to name a few. In spite of the astonishing
diversity in structure and chemical nature displayed by these molecules, all
of them present antimicrobial activity, a condition that has led researchers
to consider them as natural antibiotics and as such a new and innovative
alternative to chemical antibiotics with a promising future as biotechnological
tools. A resulting new generation of anti microbial peptides (AMPs) with higher
specific activity and wider microbe-range of action could be constructed, and
hopefully endogenously expressed in genetically-modified organisms.
Keywords: applied biotechnology, innate response, natural antibiotics.
The
continuous use of antibiotics has resulted in multi-resistant bacterial strains all
over the world and as expected, hospitals have become breeding grounds for
human-associated micro organisms (Mainous and Pomeroy, 2001).
Nonetheless, the same time-bomb effect is slowly developing with animal-associated
pathogens in commercially driven activities, such as aquaculture and confined
poultry breeding, where the indiscriminate use of antibiotics is perceivedasessential
for industries survival. Consequently, there is an urgent need to search
for alternatives to synthetic antibiotics. The discovery of two classes of antimicrobial
peptides, non-ribosomally synthesized (Hancock and Chapple,
1999) - present in bacteria - lower eukaryotes and plants - and ribosomally-synthesized
peptides, of wider distribution (Boman, 1995; Broekaert
et al. 1997; Hancock and Lehrer, 1998; Hoffmann
et al. 1999; Thevissen et al. 1999; Zasloff,
2002; Ezekowitz and Hoffmann, 2003), provided a new
therapeutic strategy to fight micro organisms. Recent studies show that several
cationic and non-cationic peptides expressed in many vertebrate, invertebrate
and bacterial species (Lüders et al. 2003) act synergistically
to improve immune responses.
The knowledge
acquired in the past two decades and the discovery of new groups of antimicrobial
peptides make natural antibiotics the basic element of a novel generation
of drugs for the treatment of bacterial and fungal infections (De
Lucca, 2000; Hancock, 2000; Welling
et al. 2000; Selitrennikoff, 2001). In addition, the
wide spectrum of antimicrobial activities reported for these molecules suggests
they potential benefit in the treatment of cancer (Tanaka,
2001) and viral (Chinchar et al. 2001; Andersen
et al. 2001; Chernysh et al. 2002) or parasitic infections
(Vizioli and Salzet, 2003). Different therapeutic applications
of these compounds, from topical administration to systemic treatment of
infections, have been developed by several biotechnological companies (Hancock,
2000; http://www.inimexpharma.com; http://biotech.deep13.com/Alpha/alpha.html;
http://www.geniconsciences.com/) Interestingly, to date, clinical
Phase I and II trials have shown a limited resistance for the bacterial strains
tested (Zasloff, 2002). These features make the antibiotic
peptides a powerful arsenal of molecules that could be the antimicrobial
drugs of the new century as an innovative response to the increasing problem
of MDR (http://www.multi-drug-resistance.org; http://www.multi-drug-resistenz.de; http://www.demegen.com.)
Resistance
to chemical antibiotics: an unsolved and growing problem
It
is widely accepted among clinicians, medical researchers, microbiologists
and pharmacologists, that antibiotic resistance will, in the very near future,leave
healthcare professionals without effective therapies for bacterial infections.
As an example, it is now estimated that about half of all Staphylococcus
aureus strains found in many medical institutions are resistant to antibiotics
such as methicillin (Roder et al. 1999). The emergence
among enterococci of resistance to another useful and widely effective antibiotic,
vancomycin (Novak et al. 1999), might accelerate the spread
of vancomycin-resistant genes, via plasmids, throughout other species, eventually
limiting the efficacy of this drug. Consequently, the priority for the next
decades should be focused in the development of alternative drugs and/or
the recovery of natural molecules that would allow the consistent and proper
control of pathogen-caused diseases. Ideally, these molecules should be as
natural as possible, with a wide range of action over several pathogens,
easy to produce, and not prone to induce resistance.
The
new generation of native peptide molecules, also known as Anti Microbial
Peptides (AMPs), isolated from a full range of organisms and species from
bacteria to man, seem to fit this description. As a consequence, they have
been termed natural antibiotics, because they are active against a large
spectrum of microorganisms, including bacteria and filamentous fungi - in
addition to protozoan and metazoan parasites (Liu et al. 2000; Vizioli
and Salzet, 2003). All of these molecules are key elements directly implicated
in the innate immune response of their hosts, which includesthe expression
of fluid phase proteins that recognize pathogen-associated molecular patterns,
instead of specific features of a given agent to
promote their destruction. As a result, the response is very fast, highly
efficient and applicable to a wide range of infective organisms (Hoffmann
and Reichhart, 2002). Additionally, the effect of AMPs can go beyondisolated
bacterial cells, as shown by the inhibition they can exert over clusters
of pathogenic bacteria, such in biofilm development (Singh
et al. 2002).
The
importance of the innate immune response in living organisms
In order
to survive in a world laden with microorganisms, most multi-cellular organisms
ought to depend on a network of host defense mechanisms which in most cases,
involves several levels of interacting systems. Since the initial contact
of fastidious microorganismswith the host usually occurs at inner or outer
body surfaces, they should be the primary site for an immune reaction to
occur. Thus, innate immune responses refer to the first line of host defense,
which acts within a few hours after microbial exposure to mucosal surfaces.
Upon recognition of conserved molecular microbial patterns such as PAMs or
Pathogen-Associated Molecular Patterns (e.g. LPS and cell wall components)
and Toll-like receptors (TLR) ( Hoffman et al. 1999; Aderem
and Ulevitch, 2000; Akira et al. 2001) initiate the
immune responses of the host. Using the urinary and gastro-intestinal tract
as model systems, information has been obtained on how organ- and cell-specific
expression patterns of TLR on epithelial cells correlate to the ability of
an organ to rapidly respond to bacterial infections has been obtained( Bckhed et
al. 2003). It has become clear now that understanding the innate response
to pathogens will certainly provide insights to host defenses as well as
the strategies used by pathogens to circumvent these defense mechanisms.
Remarkably, the pattern-specific recognition system already acknowledged
in animals, has also been reported in plants ( Dangl and Jones,
2001).
In
complex system suchas humans, an invading microorganism can simply be eliminated
by this primary reaction - the innate response - without requiring an activation
of the adaptive immunity, the next step in this complex cascade (Bals,
2000). If the invading microbe outgrows the innate host defence, endogenous
effector mechanisms of the innate system are up-regulated and have direct
antimicrobial activity and mediator function to attract inflammatory cells
and cells of the adaptive immune system. In lower eukaryotes, mostly invertebrates,
the adaptive system is nonexistent, thus accounting for the versatile and
effective role the innate system has in order to control, by itself, the
invasiveness of a given pathogen (reviewed by Otvos, 2000).
Differentiating antimicrobial
peptides
Memberss
of the major groups of antimicrobial peptides have been classified mainly
on the basis of their biochemical (net charge) and/or structural features
(linear/circular/amino acid composition), looking for common patterns that
might help to distinguish them. (Tossi and Sandri, 2002; Zasloff,
2002). The resulting most important groups are the following:
From
Eukaryotes
Cationic
peptides: This is the largest group and the first to be reported,
being widely distributed in animals and plants. So far, more than a thousand
of such peptides have been characterized and over 50 % of them have been
isolated from insects (Bulet et al. 1999; Andreu
and Rivas, 1998; http://www.bbcm.univ.trieste.it/~tossi/antimic.html).
On the basis of their structural features, cationic peptides can be divided
as well into three different classes: (1) linear peptides forming-helical
structures; (2) cysteine-rich open-ended peptides containing single or
several disulfide bridges; and (3) molecules rich in specific amino acids
such as proline, glycine, histidine and tryptophan.
Important
subfamilies of cationic peptides include:
-
Defensins: This
isa highly complex group of 4-kDa open-ended cysteine-rich peptides arranged
with different structural motifs. They have been mostly isolated from
mollusc, acari, arachnids , insects, mammals and plants. Defensins
are arranged in families, based on their structural differences. Invertebrates
( Hubert et al. 1996; Andreu and Rivas,
1998; Dimarcq et al. 1998; Bulet
et al. 1999; Mitta et al. 1999; Silva
et al. 2000; Nakajima et al. 2001) and plant ( Broekaert
et al. 1997; García-Olmedo et al. 1998; Segura
et al. 1998; Liu et al. 2000) defensins are characterized
by three and four disulfide bridges, respectively. They show a common
structure comprising an ά-helix linked to a β-sheet by two
disulfide bridges, distinctive structure known as the CSab motif.In mammals, ά -
and β-defensins are characterized by an antiparallel -β sheet
structure, stabilized by three disulfide bridges ( Zasloff,
2002). Some of them naturally exist as cyclic molecules such as the
theta-defensins ( Tang et al. 1999; Lehrer
and Ganz, 2002). It has been difficult to determine whether all molecules
are homologous or have independently evolved similar features, but evidences
are in favour of a distant relationship. The best evidence of this relationship
is structural, particularly from their overall three-dimensional structure
and from the spacing of half-cystine residues involved in intra-chain
disulfide bonds.
- Thionins: These
are antimicrobial, and generally basic, plant peptides with a molecular
weight of 5000 Da, which contain 6 or 8 conserved cysteine residues. Their in
vitro toxicity against plant pathogenic bacteria and fungi indicates
a role in the resistance of plants (Bohlmann, 1999). Ligatoxin
B, a new basic thionin containing 46 amino acid residues has been recently
isolated from the mistletoe Phoradendron liga (Li
et al. 2002). Similarities observed by structural comparison of the
helixturnhelix (HTH) motifs of the thionins and the HTH DNA-binding proteins,
led the authors to propose that thionins might represent a new group of
DNA-binding proteins.
- Amino
acid-enriched class: This is a distinctive class of antibacterial
and antifungal cationic peptides, enriched in specific amino acids, with
distinctive features depending on the organism from which they are isolated
. Those proline- and glycine-rich are mostly from insects and active
against Gram-negative bacteria (Bulet et al. 1999; Otvos,
2000); while cysteine-rich peptides, not related to defensins, represent
the most diverse family among arthropods (Dimarcq et al.
1998). On the other hand those enriched in histidine are particularly
basic, mostly from mammals (Pollock et al. 1984). Among
them, histatin recovered from saliva from humans and primates and primarily
directed against fungal pathogens, outstands for its distinctive mechanism
of action which does not involve channel formation in the fungal cytoplasmic
membrane but rather translocates efficiently into the cell and targets
the mitochondrion (Tsai and Bobek, 1998). Those
enriched in histidine and glycine are quite large, also affecting fungal
pathogens and a distinctive feature is that their residues are arranged
in approximately regular but different structural repeats (Tossi
and Sandri, 2002). Finally, only two peptides enriched in tryptophan
residues have been described, both derived from porcine cathelicidin
precursors (Schibli et al. 2002). The outstanding feature
though, is broad spectrum of activity including hundreds of Gram-positive
and negative clinical isolates in addition of fungi and even the enveloped
HIV virus (Gennaro and Zanetti, 2000).
- Histone
derived compounds: This is a family of cationic helical peptides
corresponding to cleaved forms of histones originally isolated from
toad (buforin) (Park et al. 1996) and fish epithelia
(parasin) (Park, 1998). These molecules are structurally
similar to cecropins and quite active against bacteria and fungi. In
the case of buforin II, at least, it was demonstrated that this molecule
penetrates bacterial membranes and bind to nucleic acids thus interfering
with cell metabolism and leading to rapid cell death (Park
et al. 1998). AMPs are important factors in fish innate immunity
(Iwanaga et al. 1994; Lemaitre et al.
1996; Zhou et al. 2002) and new contributions
tend to demonstrate it. Recently, an active peptide was identified both
in coho salmon mucus and blood, which display full identity with the
N-terminus of trout H1 histone (Patrzykat et al. 2001).
This is an indication that histone proteins may be a relatively ubiquitous
component of host defenses (Hirsh, 1958). This assumption
has been strengthened in recent years by the isolation of histone-like
proteins in the cytoplasm of murine macrophages (Hiemstra
et al. 1993) and the characterization of histone H2B fragments in
human wound fluids (Frohm et al. 1996).
- Beta-hairpin: The
third class of cationic peptides known includes a wide range of 2 to 8-kDa
compounds containing beta-hairpin cross-linked by disulphide bridge(s) .
The smallest members of this class with one disulfide bridge, is represented
by thanatin and brevinin. Those containing two disulfide bridges are represented
by androctonin (Mandard et al. 1999) tachyplesin and
protegrin I (Mandard et al. 2002). Members of
this latter group are 2-kDa hairpin-structured peptides, isolated from
both invertebrates and vertebrates and show preferential antibacterial
and antifungal activities (Dimarcq et al. 1998; http://www.sanger.ac.uk/Users/sgj/thesis/node53.html).
- Other
natural structural and functional proteins: Cationic peptides have
been successfully recovered from precursor proteins others than hemocyanin,
such as hemoglobin in tick (Fogaca et al. 1999) and
lactoferrin in human (Andersen et al. 2001). Recently,
a fraction enriched in a novel antibacterial domain from the N-terminal
part of caprine lactoferrin (fragment 14 42) has been recovered from
its precursor protein bound to a cation-exchange membrane, followed by in-situ enzymatic
cleavage with an appropriate enzyme and referred as lactoferricin-C (Jones
et al. 1994). Additionally, the Lactoccocus lactis lantibiotic
nisin was also successfully released from its precursor polypeptide
by the same procedure (Recio et al. 2003). The purification
procedure described above could be used to isolate cationic peptides
produced in bacteria as inactive fusion proteins or from naturally occurring
antibacterial peptides by specific digestion from their precursors.
Two
other forms of precursor-derived peptides are represented by cathelicidins
and thrombocidins. The formers are quite abundant in mammals and generated
from precursor proteins bearing an amino-terminal cathepsin L inhibitor domain
(cathelin) (Lehrer and Ganz, 2002). The latters are compounds
released from platelets and arise from deletions of the CXC chemokines neutrophil-activating
peptide 2 and connective tissue-activating III in humans (Krijgsveld
et al. 2000).
In
plants, a similar picture is slowly emerging. A new family of antimicrobial
peptides has been described from Macadamia integrifolia of which the
first purified member has been termed MiAMP2c (Marcus et al.
1997). The peptide, active against a number of plant pathogens in
vitro, derives from a precursor protein similar to vicilins 7S globulin
proteins, suspected of a putative participation in defense during seed germination
(Marcus et al. 1997). The novel peptide is inserted in
the highly hydrophilic N-proximal region of the precursor, where three additional
cysteine-containing MiAMP2c-like patterns exist, suggestive of three additional
peptide isoforms, a pattern already described for fish AMPs (Lauth
et al. 2002).
Proposed
mechanism of action of cationic peptides
In
spite of the fact that the mechanism of action is not satisfactory established
for all cationic peptides, the structural model established by Shai-Matzusaki-Huang
(Matzusaki, 1999) provides a reasonable explanation for
most antimicrobial activities of these compounds (Zasloff,
2002). The model proposes that these linear amphipatic-helical peptides interact
with bacterial membranes and increase their permeability, either by the effect
of their positive charges with anionic lipids of the target membrane or by
membrane destabilization through lipid displacements due to the drastic changes
in the net charge of the composed system. A similar mechanism has been proposed
for the cysteine-rich peptides such as defensins, which are suggested to
form ion-permeable channels in the lipid bilayer. In contrast, some peptides
penetrate into cells to exert their action over target molecules (Kragol
et al. 2001). Several additional hypotheses have been proposed to explain
the mechanisms by which peptides kill target cells; such hypotheses include
induction of hydrolases which degrade the cell wall, disturbance of membrane
functions and damage to crucial intracellular targets after internalization
of the peptide (Zasloff, 2002).
Anionic
peptides: This is a smaller novel group of molecules displaying antimicrobial
activity which, up to now, have been mostly isolated from mammals.
- Neuropeptide
derived molecules: This is the first class of anionic compounds
recently found in infectious exudates of cattle and humans. They mostly
include peptides derived from the processing of neuropeptide precursors
such as pro-enkephalin-A, to yield active peptide B and enkelytin; some
of them are phosphorylated (Salzet and Tasiemsky, 2001).
These peptides are mainly active against Gram-positive bacteria at micromolar
concentrations, likecationic peptides, and similar products have been
reported in some invertebrate species (Salzet, 2001).
- Aspartic-acid-rich
molecules: Peptides of this class have been isolated and characterized
primarily fromcattle pulmonary surfactants (Brogden et
al. 1996; Bals, 2000; Fales-Williams
et al. 2002). They have a structure similar to the charge-neutralizing
pro-peptides of Group I serine proteases and have been proposed to regulate
the activity of pulmonary enzyme systems in these animals. Recently,
a novel anionic 47-amino-acid peptide, named dermicidin, has been identified
in human sweat, in response to a variety of pathogenic Gram-positive
bacteria and ascribed to this class of molecules (Schittek
et al. 2001).
- Aromatic
dipeptides: The aromatic dipeptides comprise low molecular weight
antibacterial compounds primarily isolated from dipteran larvae. There
areonly two well characterized members: the N--alanyl-5-S-glutathionyl-3,4-dihydroxy-phenylalanine
(573 Daltons), identified in the flesh fly Sarcophaga peregrina (Leem,
1999; Akiyama et al. 2000), and the p-hydroxycinnamaldehyde,
isolated from the saw fly Acantholyda parki (Leem
et al. 1999). The mode of action of these molecules is, at present,
unknown.
- Oxygen-binding
proteins: Peptides derived from oxygen-binding proteins,
or hemocyanin derivatives (Destoumieux-Garzon et al. 2001; Muñoz
et al. 2002; Muñoz et al. 2003), are the first
representatives of the group of peptides derived from oxygen-binding
proteins recently isolated from the hemolymph of arthropods and annelids
species. Another molecule, detected in tick hemolymph, is a cleaved form
of vertebrate hemoglobin, processed by the parasite after blood meal
ingestion (Fogaca et al. 1999). These proteins have
been reported as bactericidal compounds and might be considered as a
reservoir of defense molecules to be used as integrative weapons to fight
pathogens (Vizioli and Salzet, 2002). Bactericidal
activity of anionic peptides, oxygen-binding protein derivatives and
aromatic dipeptides are not as potent as cationic peptides, and their
physiological relevance remains to be established in order to define
their importance as components of the innate response (Decker
et al. 2001).These molecules, whose mode of action could differ from
that of cationic peptides and other antibiotics, could complement the activity
of other compounds and constitute a useful base to develop novel synthetic
derivatives.
From
Prokaryotes:
The
antimicrobial peptides produced by bacteria have been grouped into different
classes based upon the producer organisms, molecular size, chemical structure
and mode of action, which resulted in different names for putative compounds
which turned out to be identical: (thiolbiotics, lantibiotic microcin, colicin,
bacteriocin, to name a few) (Kolter and Moreno, 1992).
The most relevant active-membrane peptides among them are produced by gram-positive
bacteria and classified taxonomically as bacteriocins (Oscáriz
and Pisabarro, 2001). Some of them have been the center of attention
because of their application as food preservatives (Schillinger
et al. 1996).
Bacteriocins,
cationic, neutral and anionic in chemical nature, are all in the range of
1.9 (Actagardine) and 5.8 (Lactococcin B) kDa in molecular mass (Jack
et al. 1995), cationic, neutral and anionic in chemical nature (Oscáriz
and Pisabarro, 2001). The most thoroughly studied bacteriocins are those
produced by lactic-acid bacteria, of which sakacins seem to be most unique
(Jack et al. 1995; Simon et al. 2002),
and the lantibiotics, which contain modified amino acid residues (Oscáriz
and Pisabarro, 2001). Another representative, pediocins, are usually
co-transcribed with a gene encoding a cognate-immunity protein (Fimland
et al. 2002). The 44-amino acid pediocin produced by Pediococcus acidilactici strains
is encoded in an 8.9 kb plasmid.
The
importance of AMPs in humans
Peptides
of the defensin, cathelicidin, thrombocidin and histatin classes are found
in humans protecting epithelia against invading microorganims and assisting
neuthrophils and platelets (Peschel, 2002). In the airways, α-and-β-defensins
and the cathelicidin LL-37/hCAP-18 are produced by the respiratory epithelium
and alveolar macrophages and then secreted into the airway surface fluid
(Wang et al. 1999). Beyond their antimicrobial function,
these peptides are known to be multi-functional. In fact, it has been demonstrated
their multiple roles as mediators of inflammation with effects on epithelial
and inflammatory cells, and the impact these roles have over such diverse
processes as proliferation, immune induction, wound healing, cytokine release,
chemotaxis, proteaseantiprotease balance, and redox homeostasis (Ganz,
2002; Cole et al. 2003; Com et al. 2003; Liu
et al. 2003).
Discussion
Is there an induced
resistance to AMPs?
Considering
that AMPs are natural barriers to bacterial infections, pathogens ought to
have developeda variety of strategies that render them resistant to antimicrobial
host defenses. The only currently available structural model explaining the
mechanism of action of AMPs (Shai-Matzusaki-Huang) (Matzusaki,
1999), the action of these peptides is from the outside and over the
pathogens membrane either by increasing their permeability or by destabilizing
membranes by changing the net charge of the composed system. Since biological
membranes are indeed dynamic fluids, the generation of resistance appears
to be less likely to occur. Nonetheless, pathogens have evolved countermeasures
not to resist, but at least to limit AMPs effectiveness, such as chemical
modifications and/or alternation of energy-dependent pumps at the membrane
level (Peschel, 2002). The same is true for intracellular
bacterial pathogens, in which resistance-limitation is less effective against
mostly cationic peptide-driven antimicrobial activity existing in the phagosomes
of circulating monocytes, neutrophils and some mucosal epithelial cells (Ernst
et al. 1999). Additionally, the fact that the common features for most
peptides are a net positive charge and an amphipathic nature, allows them
to persist at water-lipid interfaces and then to disturb microbial membrane
components (Ruissen et al. 2001).
AMPs
and biotechnology: Is there a promising future?
Good
progress has been achieved with respect to defining the rules by which the
immune system works and its complexity and interconnections are being slowly
understood. In this perspective, the innate immune response has been neglected,
but the consolidation of new discoveries in the field is slowly repositioning
it (Fearon, 2000; Nathan, 2002). Nonetheless,
the potential massive use of these natural compounds is hampered by the limited
amount that can be extracted in vivo as well as non-optimal specific
activities, which would require huge amounts for clinical and therapeutical
application. This is the point where biotechnology should play a pivotal
role in the near future, independent that chemical synthesis of peptides
could also be a non exclusive alternative. Classically, these peptides
are encoded by small genes, with conserved sequences and patterns that make
their cloning easy, and should allow easy expression and both small- and
large scale purification (Uteng et al. 2002). From a more
innovative point of view, gene amplification and transgenesis seem like feasible
ways to increase production and enhance specific activity of selected molecules. But,
is this possible to achieve in vivo? The answer is, once again,
yes. Biosynthetic and preparative production of AMPs have been successfully
reported (Haught et al. 1998; Martemyanov
et al. 2001), as have synthetic forms of AMP analogues displaying enhanced
antimicrobial activity (Cudic et al. 2003). There are some
additional examples: Since AMPs were first characterized in insects, a great
deal of complementary work comes from that area of applied research. One
of the most notable pieces of work deals with Drosophila mutants not
expressing any known endogenous AMP genes and, as a consequence, highly susceptible
to bacterial infections. Genetic manipulation of these mutants complemented
with a single constitutively expressed AMP gene can rescue susceptibility
to infections (Tzou et al. 2002). In plants, as expected,
tobacco has been thetarget for successful engineered-production of mammalian
AMPs (Morassutti et al. 2002), as well as amphibian anti
microbial peptides, where vertical transmission of resistance occurs (Ponti
et al. 2003). In addition, AMPs from other origins have been added
to confer disease resistance in transgenic tobacco and banana (Chakrabarti
et al. 2003) and potato (Osuky et al. 2000), thus opening
unsuspected alternatives to provide agronomically relevant levels of disease
control worldwide (Van der Biesen, 2001).
Relevancy
of AMPs: Is there more to come?
Although
at present AMPs are believed to exerttheir primary activity on bacterial
membranes, new evidence is suggesting that AMP activity might be broader,
including selective inhibition of intracellular targets (Cudic
and Otvos, 2002). It is thought that cationic peptides might induce genomic
responses in bacteria treated with AMPs, in addition to any lethal effect
on the bacterial membrane. This appears to be the case, as recently
demonstrated (Hong et al. 2003). These authors have shown
that the transcription profiles of at least 26 Escherichia coli genes
change specifically and significantly after exposure to lethal and sub lethal
concentrations of Cecropin A, an emblematic cationic peptide. Moreover, half
of these transcripts corresponded to proteins of unknown function, which
makes these observations quite intriguing.
Now,
regarding the wide variety and diverse classes of natural peptides, we must
add necessarily, the processing alternatives, which are slowly being reported
that might make these molecules incommensurable, approaching the diversity
of immunoglobulins. The case of lactoferricin-C, generated as a functional
internal domain of caprine lactoferrin in a manner mimicking the generation
of inteins (selfish DNA elements inserted in-frame and translated together
with their host proteins: http://bioinfo.weizmann.ac.il/~pietro/inteins),
opens a new and broad area of research. Something similar occurs with milk-derived
compounds, where it is clear that milk contains a group of proteins, which
perform a protective function. These proteins harbor in their primary sequence,
peptides that are inactive in the parent protein and that are released during
gastrointestinal digestion or food processing (Yamauchi, 1992).
In contrast, the generation of thrombocidin, arising from carboxy-terminal
deletions of key neuthrophil- and connective tissue-activating peptides in
humans, broadens the spectrum of alternative for processing associated with
the generation of AMPs. Additionally, slight variations in the structure
of preexisting peptides might broaden their potential as AMPs. A good example
is that of histatin-5, a naturally occurring anti-fungal peptide in human
saliva, which presents at least two variants (dhvar4 and dhvar5) displaying
increased anti-microbial activity by subtle changes in their amphipathicity,
a good indicator of membrane destroying activity, which allows them to be
internalised showing a more destructive effect on mitochondria than on external
membranes (Ruissen et al. 2001). Therefore, it is reasonable
to think that a number of existing functional proteins, unrelated to immune
responses, might contain potential and fully active AMPs This is a complementary
strategy to that of natural anti-microbial peptides, which by themselves
might adjust to potential bacterial adaptations to counteract their pathogenicity.
This is only the tip of the iceberg in this appealing topic. The recent
proposalthat antibody multi specificity can be mediated by conformational
diversity of pre existing isomers to increase the effective size of the antibody
repertoire (James et al. 2003), is perfectly applicable
to understand diversity of existing AMPs as well as the potential of those
derived from multiple and heterogeneous type of precursors.Only time will
verify these assumptions.
Structure
and representative Peptides
|
Organism |
Antimicrobial
activity |
References |
Linear α-helix
peptides
Cecropins |
Insects, pig |
Bacteria, fungi, virus, |
Andreu and Rivas, 1998; Putsep
et al. 1999; Zasloff, 2002; Vizioli
and Salzet, 2003 |
Clavanin,
styelin |
Tunicates |
Bacteria |
Zasloff,
2002 |
Megainin,
dermaseptin |
Amphibians |
Bacteria,
protozoa |
Zasloff,
2002, Vizioli and Salzet, 2003 |
Buforins |
Amphibians |
Bacteria,
fungi |
Park
et al. 1996, 1998; Zasloff, 2002 |
Pleurocidin |
Fish |
Bacteria,
fungi |
Cole
et al. 2000 |
Moronecidin |
Fish |
Bacteria |
Lauth
et al. 2002 |
Linear
peptides amino acid-rich |
|
|
|
Pro-rich: |
|
|
|
Drosocin,
metchnikowins |
Fruit
fly |
Bacteria |
Bulet
et al. 1999 |
Pyrrhocoricin |
Hemipteran |
Bacteria,
fungi |
Bulet
et al. 1999 |
metalnikowin |
Hemipteran |
Bacteria,
fungi |
Bulet
et al. 1999 |
Gly-rich: |
|
|
|
Diptericins,
attacins |
Dipterans |
Bacteria |
Bulet
et al. 1999 |
shepherin
I and shepherin II |
Plants |
Bacteria
G- , fungi |
Park
et al. 2000 |
Ac-AMP1-
Ac-AMP2 |
Plants |
Bacteria
G+, fungi |
Broekaert
et al. 1992 |
His-rich |
|
|
|
Histatin |
Human |
Bacteria,
fungi |
Andreu
and Rivas, 1998; Zasloff, 2002 |
shepherin
I and shepherin II |
Plants |
Bacteria
G- , fungi |
Park
et al. 2000 |
Try-rich |
|
|
|
Indolicidin |
Cattle |
Bacteria |
Andreu
and Rivas, 1998; Zasloff, 2002 |
Tritrpticin,
lactoferrin B, LfcinB4-9 |
Eukaryots |
Bacteria |
Schibli
et al. 2002 |
Single
disulfide bridge |
|
|
|
Thanatin |
Hemipteran |
Bacteria,
fungi |
Dimarcq
et al. 1998; Bulet et al. 1999; Zasloff,
2002 |
Brevinins |
Frog |
Bacteria |
Andreu
and Rivas, 1998; Zasloff, 2002 |
Lanthionins |
Bacteria
G+ |
Bacteria |
Hancock,
2000 |
Two
disulfide bridges |
|
|
|
Tachyplesin
II |
Horseshoe
crab |
Bacteria,
fungi, virus |
Andreu
and Rivas, 1998, Dimarq et al. 1998; Zasloff,
2002 |
Androctonin |
Scorpion |
Bacteria,
fungi |
Dimarq
et al. 1998; Zasloff, 2002 |
Protegrin
I |
Pig |
Bacteria,
fungi, virus |
Zasloff,
2002 |
Three
disulfide bridges |
|
|
|
α Defensins |
Mammals |
Bacteria,
fungi |
Andreu
and Rivas, 1998; Zasloff, 2002 |
β Defensins |
Mammals |
Bacteria,
fungi |
Andreu
and Rivas, 1998; Zasloff, 2002 |
Defensis |
Insects |
Bacteria,
fungi, protozoa |
Dimarq
et al. 1998; Bulet et al. 1999; Vizioli
and Salzet, 2003 |
Penaeidins |
Shrimp |
Bacteria,
fungi |
Dimarq
et al. 1998; Bulet et al. 1999; Vizioli
and Salzet, 2003 |
More
than three disulfide bridges |
|
|
|
Tachycitin |
Horseshoe
crab |
Bacteria,
fungi |
Dimarq
et al. 1998 |
Drosomycin |
Fruit
fly |
Fungi |
Dimarq
et al. 1998 |
Gambicin |
Mosquito |
Bacteria,
fungi, protozoa |
Vizioli
et al. 2001 |
Heliomicin |
Lepidopteran |
Bacteria,
fungi |
Lamberty
et al. 2001 |
Plant
defensins |
|
|
|
defensin
protein WT1 |
Plants |
Fungi |
Saitoh
et al. 2001 |
alfAFP
defensin |
Plants |
Fungi |
Gao
et al. 2000 |
cysteine-rich |
Plants |
Bacteria
, fungi |
Tailor
et al. 1997 |
So-D1-7 |
Plants |
Bacteria
,fungi |
Segura
et al.. 1998 |
DmAMP1 |
Plants |
Fungi |
Thevissen
et al. 2000 |
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