Antimicrobial Agents and Chemotherapy, June 1999, p. 1317-1323, Vol. 43, No. 6
Peptide Antibiotics
Department of Microbiology and Immunology,
University of British Columbia, Vancouver, British Columbia, Canada V6T
1Z3,1 and Metalloprotein Research Group,
Division of Biochemistry and Molecular Biology, United Medical and
Dental School of Guy's and St. Thomas's Hospitals, Guy's Hospital,
London SE1 9RT, United Kingdom2
Hundreds of peptide antibiotics have
been described in the past half-century (20, 28, 35). These
fall into two classes, non-ribosomally synthesized peptides, such as
the gramicidins, polymyxins, bacitracins, glycopeptides, etc., and
ribosomally synthesized (natural) peptides. The former are often
drastically modified and are largely produced by bacteria, whereas the
latter are produced by all species of life (including bacteria) as a major component of the natural host defense molecules of these species.
The former have been well described to date (28, 35) and
will be briefly summarized here with emphasis on their clinical importance, similarities in function to the natural peptides, and
future prospects. The latter represent a new opportunity for the
medicinal chemist and will be described in more detail with emphasis on
the role in natural host defenses (as nature's antibiotics) and the
clinical potential of peptides derived from these natural peptides.
Introduction.
Nonribosomally synthesized peptides can be
described as peptides elaborated in bacteria, fungi, and streptomycetes
that contain two or more moieties derived from amino acids (28,
35). By definition even the longer peptidic molecules in this
class are made on multienzyme complexes rather than being synthesized,
in the normal method of proteins, on ribosomes (as pre-pro-proteins in
the case of the ribosomally synthesized peptides considered below). By
this definition, many of the antibiotics used in our society are
peptide derived. For example, the natural penicillins can be dissected
into residues of monosubstituted acetic acid, L-cysteine
and D-valine, while cephalosporin C, the basic building block of many semisynthetic cephalosporins comprises
D- Biosynthesis.
A large amount of information has shown that
nonribosomal peptide synthesis is performed according to the
multiple-carrier thiotemplate mechanism (40). In this
template-driven assembly, a series of very large multifunctional
peptide synthetases, with a modular arrangement, perform the peptide
synthesis in an ordered fashion. A single peptide synthetase gene
(e.g., grsB of the gramicidin S biosynthetic operon
[38]) can be as large as 13 kb (4,300 amino acids) and
contain four to six modules (resulting in the addition of four to six
residues). Each module contains the basic ability to recognize a
residue, activate it, modify it as necessary, and add it to the growing
peptide chain. The minimal module is capable of activating one amino
acid or hydroxyacid residue, stabilizing the activated residue as a
thioester, and polymerizing it in its correct sequence to the
previously added residue with the aid of a covalently attached
cofactor, 4'-phosphopantotheine. This basic mechanism can result in a
great chemical variety of peptide products containing hydroxy-,
L-, D-, or unusual amino acids, which can be
further modified by N methylation, acylation, glycosylation, or
heterocyclic ring formation. More than 300 different residues are known
to be incorporated into these peptide secondary structures. The
structures of three antibiotics
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
MINIREVIEW
INTRODUCTION
Top
Introduction
References
NONRIBOSOMALLY SYNTHESIZED PEPTIDES
-aminoadipic acid, L-cysteine,
,
-dehydrovaline, and acetic acid. Also, the glycopeptide class of
antibiotics, including vancomycin and teicoplanin, have
sugar-substituted peptide backbones. However, given the enormous volume
of literature on these and the large number of peptides that are not
used in the clinic, we are restricting ourselves here to the
high-molecular-weight peptide antibiotics which have been used clinically.
bacitracin, gramicidin S, and
polymyxin Bthat are used clinically are listed in Table
1.
TABLE 1.
Examples of primary amino acid sequences of natural
antimicrobial peptides
Activities and mechanisms of action. Two of the peptides described in Table 1 are cationic in nature, with polymyxin B having a net charge of +5 and gramicidin S having a charge of +2. Polymyxins tend to be rather gram negative selective. In contrast, gramicidin S has traditionally been considered gram positive selective. However, we recently showed that, if MIC measurements are done in the correct fashion, gramicidin S has excellent activity against gram-negative bacteria and the fungus Candida albicans (29). With this caveat, the accumulated data suggests that these cationic antibiotics act in exactly the same way on cells as the cationic antimicrobial peptides described below (i.e., self-promoted uptake across the cytoplasmic membrane followed by interference with the cytoplasmic membrane barrier).
In contrast, the gram-positive-specific antibiotic bacitracin works by inhibiting the transfer of cytoplasmically synthesized peptidoglycan precursors to bactoprenol pyrophosphate. Other antibiotic peptides of nonribosomal origin, the streptogramins, are protein synthesis inhibitors.Clinical applications. Colimycin, the methosulfate derivative of the cationic lipopeptide colistin (polymyxin E), has been utilized quite successfully in an aerosol formulation against Pseudomonas aeruginosa lung infections (25). Colimycin appears to be well tolerated. The major reason for chemically modifying the natural lipopeptide is to decrease systemic toxicity. Such toxicity may be partially due to the lipid tail appended to the nonapeptide, but it is our understanding that even the deacylated derivative of polymyxin (polymyxin B nonapeptide) tends to be too toxic for human systemic use. Indeed, the nonacylated cyclic decapeptide gramicidin S is also quite toxic, causing erythrocyte lysis at concentrations only threefold higher than the MIC for many bacteria (29, 30). For this reason such peptides are restricted to topical applications. Polymyxin B, together with gramicidin S and bacitracin, is a very highly utilized topical preparation. Aerosol applications of colistin are also under active consideration.
Future prospects. Although most of the nonribosomal antimicrobial peptides described here have been known for decades, many others with antibiotic activity have been described in the literature, and these peptides offer a potentially rich source of novel antimicrobials. Three types of approaches are being undertaken. The first involves modification of existing peptides (and presumably also isolation of novel peptides from nature and modification of these). For example, the streptogramins are a family of cyclic peptides discovered in the 1950s, which are quite potent but rather insoluble. Recent work has resulted in two water-soluble, semisynthetic streptogramins, dalfopristin and quinupristin. These peptides have just completed phase III clinical trials as a combination parenteral agent (Synercid) against resistant gram-positive bacteria. A second, rather exciting approach involves the modular nature of synthesis of the nonribosomal peptide antibiotics. Schneider et al. (38) have demonstrated that one can put together a novel combination of peptide synthesis modules and arrive at a novel structure. Thus, there is great potential for obtaining significant chemical diversity in the backbone amino acids or their modifications, and a combinatorial approach to generating diversity (i.e., mixing and matching modules) is possible. The third approach is to use these structures as templates for chemical synthesis and diversity. The gramicidins are one example of this approach. Variants of gramicidin S with altered ring size, charge, amino acid sequences, hydrophobicity, etc., have been constructed and shown to have greater selectivity for bacteria than for mammalian cells (30).
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RIBOSOMALLY SYNTHESIZED PEPTIDES |
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Frog skin has been used for medicinal purposes for centuries and is still used today in South American countries. It was not until 1962 that Kiss and Michl (27) noted the presence of antimicrobial and hemolytic peptides in the skin secretions of Bombina variegata, and this led to the isolation of a 24-amino-acid antimicrobial peptide named "bombinin" (12). In 1972, an antimicrobial and hemolytic peptide, melittin, was isolated from bee venom (17) and became the basis for extensive research into the structure and mechanism of action of this type of cationic antimicrobial peptide. While the hemolytic nature of melittin prevented its exploitation as a new antimicrobial, it has led to the isolation of numerous naturally occurring cationic peptides with antimicrobial activity and limited, or no, hemolytic activity (6, 8, 10, 16, 20, 31).
Antimicrobial, ribosomally synthesized, cationic peptides have been recognized only recently as an important part of innate immunity (6, 8, 21) found throughout the evolutionary tree. However, examination of these peptides has shown general trends but little sequence homology, and this suggests that each peptide has evolved (probably convergently) to act optimally in the environment in which it is produced and against local microorganisms. The lack of sequence homology makes it difficult to predict the activities of the peptides in vivo and makes it challenging to design potent synthetic antimicrobial peptides which have the desired in vivo activities. The potential of synthetic peptides as novel chemotherapeutic agents will be discussed.
Distribution of naturally occurring antimicrobial peptides.
Antimicrobial peptides are so widespread that they are likely to play
an important protective role. This section will focus on a selected
range of peptides from mammals, amphibians, insects, plants, bacteria,
and even viruses, highlighting the similarities and differences between
these peptides. By comparing peptides from all the different organisms
(20), one can examine if there is a common consensus and
whether this could be used to design potent peptides targeted against
specific organisms. However, although certain peptide structural
groups occur (-structures stabilized by disulfide bonds,
amphipathic alpha-helices, extended structures, and loops [8,
18]), and these structures tend to be amphipathic (with a
polar face and a hydrophobic face), no positional conservation of even
classes of amino acids occurs. While some weakly charged (usually
bacterium-derived) peptides exist, antimicrobial peptides generally
have two to nine excess, positively charged amino acids (arginine or
lysine). Most antimicrobial peptides have at least 50% hydrophobic
amino acid residues and a low proportion of both neutral polar and
negatively charged amino acids. Although peptides with antifungal
activity show a higher proportion of polar neutral amino acids, there
seem to be few other similarities. Since no specific rules are evident, it is probable that synthetic peptides will be necessary to determine which factors are important for antimicrobial activity within individual groups. These then will provide potential candidates for
development as antimicrobials.
Mammalian peptides.
Antimicrobial peptides isolated from
mammals can be present within the granules of neutrophils, in mucosal
or skin secretions from epithelial cells, or as the degradation
products of proteins (8). Neutrophils, which have a
dedicated antimicrobial function, contain a range of antimicrobial
proteins and peptides including bactericidal/permeability-increasing
protein, cationic antimicrobial proteins, lysozyme, lactoferrin,
bactenecins, defensins, indolicidins, and cathelicidins (16,
20). Other cell types including epithelial cells (which produce
-defensins) and platelets (which produce platelet microbicidal
proteins), etc., also produce antimicrobial substances. The most
researched mammalian peptides are the defensins (16).
Defensins have been categorized into two groups, -defensins and classical (sometimes called -) defensins (Fig.
1; Table 1). Both contain three pairs of
disulfide-linked cysteines and a high arginine content, but the
location and connectivity of the cysteines are different between the
two groups and there are also differences in other conserved amino
acids. The structure of classical defensins has been shown to
consist of a triple-stranded -sheet connected by a loop with a
-hairpin hydrophobic finger (Fig. 1), and we assume that
-defensins will have a similar structure. In mammals, the
classical defensins are present primarily within neutrophils and Paneth
cells, and the -defensins are isolated from epithelial cells,
neutrophils, and leukocytes. Defensins are also found in the fat body
in insects and the seeds of plants (8, 10). They have a
range of activities, and mammalian defensins have activities against
bacteria, fungi, and viruses (16). The proteolytic degradation of cationic proteins is thought also to contribute to the
formation of antimicrobial peptides. Antimicrobial regions on
lactoferrin (a protein with a primary function as an iron carrier) have
been liberated upon gastric pepsin digestion of lactoferrin, and an
11-amino-acid peptide in human lactoferrin has been shown to be
responsible for its antimicrobial activity (34). In these cases, the antimicrobial region may play a role in bacterial killing, both within the whole protein and as a more potent free peptide. Lactoferrin is currently being used as a nutritional supplement, which
can liberate active peptides upon gastric digestion. It is able to
reach the lower gastrointestinal tract, where it exerts its effect
(whereas oral administration of peptides by themselves would probably
result in peptide degradation, thus rendering the peptide inactive).
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Amphibian peptides. The isolation of bombinin (12) and subsequently the magainins from Xenopus species (48) led to the investigation and discovery of peptides throughout the amphibian species. For example, within Xenopus over a dozen antibiotic peptides, which are expressed not only within the granular glands of the skin but also in the cells of the gastric mucosa and intestinal tract, have been discovered (31). In the frog Phylomedusa sauvagii, the dermaseptins, a family of five antimicrobial peptides, are present, and they are notable for their good antifungal activities (33). For peptides from both amphibians, synergy is observed with combinations of the peptides. Peptides from amphibians tend to have little sequence homology. Indeed, it has been commented that no two amphibians have homologous peptides and that even within the same species there is a high degree of variation (31). However, all amphibian peptides either have been shown or predicted to form cationic amphipathic alpha-helices, e.g., magainins, dermaseptins, and buforin II, or are cysteine-disulfide loop peptides, e.g., ranalexin and the brevinins from the Rana frog species (31, 48).
Insect peptides. Insect antimicrobial peptides have been isolated from two sources. They are secreted either within the insect (e.g., the cecropins, which are found within the hemolymph of the cecropia moth [23]) or outside the body (e.g., venoms such as bee melittin [17]). Although both classes are antimicrobial, the venoms tend to have cytotoxic activities. The cecropins have a high degree of homology and are active primarily against gram-negative bacteria (8). The discovery of a porcine cecropin (8) in the upper intestinal tract indicates that this type of peptide may be more broadly distributed.
Insects can express different peptides depending on the invading microorganism. For example, Drosophila has at least seven different antimicrobial peptides in its hemolymph (22). Some of these peptides are inducible upon infection, and one subset of peptides is induced by the same types of signalling pathways (22) as those used in mammals to induce both peptides and elements of the immune response (i.e., the Tol1 signalling pathway, which results in activation of the transcriptional factor NF-
B).
Interestingly, although the peptides do not have the exquisite
specificity of the immune response, Drosophila can
discriminate between different types of invading organisms and produce
the appropriate peptide. For instance, Drosophila naturally
infected by entomopathogenic fungi exhibits an adaptive response by
producing only antifungal peptides (32). Thus, antimicrobial
peptides are thought to replace the immune response in these more
primitive organisms.
Plant peptides. Thionins were the first antimicrobial peptides to be isolated from plants (15). They are toxic towards both gram-positive and gram-negative bacteria, fungi, yeast, and various mammalian cell types (10). Other antimicrobial peptides were isolated which were found to be structurally related to insect and mammal defensins and have been named "plant defensins" (10). Whereas most antimicrobial peptides from animals and bacteria have antibacterial activity, plant defensins have a high antifungal activity (10), reflecting the relative importance of fungal as opposed to bacterial pathogens in the plant world. The plant defensins with antifungal activity can be divided into two groups: those that inhibit fungal growth through morphological distortions of the fungal hyphae and those that inhibit fungal growth without morphological distortion (10). It has been shown that these peptides can be induced in the leaves of the radish upon challenge with a fungal pathogen (again via a conserved signalling pathway), highlighting the importance of peptides in the plant defense system. Studies on the plant defensin from the seeds of Heuchera sanguinea have shown that specific, high-affinity binding sites are present on Neurospora crassa hyphae and microsomal membranes (43). Binding was shown to be competitive, reversible, and saturable. A similarity in binding affinity was found between hyphae and microsomal membrane interactions which indicates that binding sites reside on the plasma membrane. Competition studies showed that structurally related plant defensins were able to compete, but structurally unrelated antimicrobial peptides were not. Evidence suggests that binding of plant defensins to their receptor sites is linked to their antifungal effects (43).
Bacterial peptides. Antimicrobial peptides, including both cationic and neutral peptides, are secreted from both gram-positive and gram-negative bacteria. These have been classified within the bacteriocins (which also include proteins [1, 2, 24]). Bacteriocins are generally able to kill specific bacterial competitors while causing little or no harm to the host bacterium, due to posttranscriptional modification and/or specific immunity mechanisms (2). Some peptide bacteriocins, including the Escherichia coli 7-amino-acid peptide microcin C7, which inhibits protein synthesis, and the Lactococcus peptide mersacidin, which inhibits peptidoglycan biosynthesis, have specific mechanisms which inhibit bacterial functions. However, most of these peptides, e.g., nisin and epidermidin, are thought to permeabilize target cell membranes (2, 45).
Viral peptides. Viral peptides were first identified, through protein modelling, as two positively charged, highly amphipathic helices within the cytoplasmic tail of the envelope protein of HIV-1 (13). Further studies have shown these peptides, and peptides derived from other lentivirus transmembrane proteins, to have antimicrobial and cytolytic activities (42). All of these peptides have a high proportion of arginines and no lysines, but a difference in selectivity between the peptides has been observed (42).
Synthetic peptides. To permit full exploitation of peptides as new antimicrobial agents, it is important to determine their mode of action. To this end, synthetic peptides have been made by systematic variation of naturally occurring peptides, by variation of model peptide sequences predicted to form amphipathic alpha-helices, or, more rarely, by random processes. By basing a synthetic peptide on a naturally occurring peptide, it is possible to improve antibacterial activity and at the same time give insight into the mechanism of action. As an early example of this, analogues with improved antibacterial activity and low cytotoxicity were found for the cecropins, and cecropin-melittin hybrids were developed (9). Many other analogue studies appear only in the patent literature.
Bessalle et al. (5) synthesized a number of peptides named "modellins," of different lengths and hydrophobicities. They found that amphipathic peptides composed of 16 and 17 amino acids with highly hydrophobic (Trp and Phe) and hydrophilic (Lys) amino acids on opposite faces had high antibacterial and hemolytic activities. By replacing Trp or Phe with Leu, thereby reducing the hydrophobic nature of the peptide, a drastic reduction in hemolytic activity was seen, but bioactivity was only slightly decreased. They also observed that smaller peptides of only 9 or 10 amino acids had a lower antimicrobial activity and that they have a much lower alpha-helical content than the longer peptides. This led to the suggestion that smaller peptides may have a different mechanism of killing than the larger peptides. However, it is important to note that 12- to 14-amino-acid peptides like bactenecin and indolicidin derivatives (14, 47) and 10-amino-acid peptides like gramicidin S (30) can have excellent broad-spectrum antimicrobial activities. Thus, structure is more important than size. Analogous modification experiments have been undertaken to design peptides based on both sequence and amphipathicity. A model alpha-helical antibacterial peptide was synthesized by determining the most frequent amino acids in the first 20 positions for over 80 different natural sequences (44). As with many other alpha-helical peptides, this peptide was found to be unstructured in water but readily adopts an alpha-helix in a hydrophobic environment. Synthetic peptides can also be designed to improve factors such as specificity, stability, and toxicity. It was shown that all-D-amino acid magainin exhibited antibacterial activity nearly identical to that of all-L-magainin, as well as being nonhemolytic (4). The presence of D-amino acids would make the peptide highly resistant to proteolysis, and therefore it would theoretically be more stable in vivo. These studies have been based on naturally occurring peptides. It is also possible to discover potent antimicrobial peptides randomly. Combinatorial libraries allow the systematic examination of millions of peptides. Investigators have identified a number of tetra- and hexapeptides composed of L-, D-, and unnatural amino acids which exhibit antimicrobial activities against Staphylococcus aureus (7).Activities. Cationic antimicrobial peptides have a variety of activities ranging from gram negative selective to gram positive selective to broad spectrum in nature. It is important to measure MICs in the correct fashion (41, 44) since these peptides tend to precipitate at high concentrations and bind to many surfaces. The best peptides have good MICs (1 to 8 µg/ml) against a wide range of bacteria, including some of the most difficult to treat, antibiotic-resistant pathogens. They are bactericidal with very rapid killing kinetics, even around the MIC. It is also very difficult to raise mutants resistant to these cationic peptides, and there are very few naturally resistant bacteria (none are major human infectious agents). As a result of their mechanism of action (see below), some peptides have subsidiary activities that offer added side benefits, including an ability to neutralize endotoxin and synergy with conventional antibiotics especially against resistant mutants. For these reasons they appear to have excellent potential in the fight against antibiotic-resistant bacterial pathogens. Activities in animal models of both topical and systemic infections have been demonstrated (18, 19).
Individual peptides have also been shown to have a variety of interesting activities including antifungal, antiviral, antiparasitic, and anticancer activities and an ability to promote wound healing. In most cases the exact mechanisms behind these activities are not well understood.Mechanism of action. From the sequence alone it can be difficult to predict either the activity of a peptide or the secondary structure that it will form. Most of the peptides without disulfide bridges have random structures in water, and it is only when they bind to a membrane or other hydrophobic environment, or self-aggregate, that these peptides form a structure (3, 14). For example, cecropins and melittin fold into amphipathic alpha-helices in membranous environments. It is known that the dual cationic and hydrophobic nature of the peptides is important for the initial interaction between the peptide and bacterial membrane. Cationicity promotes interaction with bacterial outer and cytoplasmic membranes (20, 47). Also, hydrophobicity is important and, e.g., increasing the hydrophobic moment of magainin analogues causes increased binding of the peptide to the membrane due to increased hydrophobic interactions between lipid acyl chains and the hydrophobic helix core (46). An overview of the proposed interaction of peptides with the cell envelope membranes of gram-negative bacteria is given in Fig. 2.
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140 mV) (E). The micelle-like aggregates (D)
are proposed to have water associated with them, and this provides
channels for the movement of ions across the membrane and possibly
leakage of larger water-soluble molecules. These aggregates would be
variable in size and lifetime and will dissociate into monomers that
may be disposed at either side of the membrane. The net effect of D and
E is that some monomers will be translocated into the cytoplasm and can
dissociate from the membrane and bind to cellular polyanions such as
DNA and RNA (F).
a phenomenon that is also not visible in
electron micrographs). Still other peptides (e.g., indolicidin and
bactenecin) do not permeabilize the cytoplasmic membrane to any great
extent at their MICs, and a separate mechanism of action is suggested.
For different cationic peptides this has been proposed to be an action
on the nucleic acids of bacteria or a triggering of autolysis
(summarized in reference 47a).
The bactericidal effects of these peptides tend to be extremely fast
(i.e., 3 log order of killing within a couple of minutes at the MIC),
and therefore it is difficult to monitor the stages of bacterial
killing. Human lactoferrin peptides have a relatively slow action, and
for these peptides it has been shown that membrane potential collapses,
followed by membrane integrity, resulting in cell lysis
(11). It has also been observed that the structures of human
lactoferrin peptides alter with time once the peptides are bound to
bacterial cell wall constituents and that the peptide does not form
pores (unpublished data).
The mechanism by which antimicrobial peptides act has become a complex
issue. It is important to understand how the peptides act to fully
exploit the use of peptides as antimicrobial agents. Small sequence
changes can lead to major changes in activity (summarized in reference
20). Not only is antimicrobial activity difficult to
predict, but so are cytotoxic activities. Indolicidin has been observed
to kill autoimmune T cells but not a number of other cell lines
(37) including neuronal cells, whereas bactenecin is
cytotoxic to neuronal and glial cells (36). Other peptides are selective for tumor over normal host cells. It is also very difficult to predict which peptides will be active in vivo based on in
vitro MICs. However, many peptides do have reasonable activities in
animal models without obvious toxicity (18, 19) and thus have been considered for potential use in the clinic.
Clinical applications. Despite several preclinical studies by small biotechnology companies on the host defense peptides (19), there are unanswered concerns about production costs, lability to proteases in vivo, and unknown toxicities (see references 18, 19, and 21 for discussions of these concerns). Since there are no published preclinical studies, we have had to rely on company press releases for information (18, 19). The cationic protein rBPI21 (Neuprex; Xoma Corp., Berkeley, Calif.) has provided the greatest amount of information (16a). Although it is a cationic protein (more than 200 amino acids) rather than a peptide, we discuss it here because small cationic peptide portions of rBPI21 have the same activities as the intact molecule. In a phase II/III clinical trial of therapy against meningococcemia, rBPI21 given intravenously along with other supportive therapies resulted in a dramatic decrease in deaths. rBPI21 has excellent antiendotoxin activity but a somewhat lower antibacterial activity. Thus, it is undergoing a range of clinical trials in which endotoxin is indicated as an important factor.
Another well-studied peptide is the magainin derivative MSI-78 (Locilex; Magainin Pharmaceuticals Inc., Plymouth Meeting, Pa.). In phase III trials of 926 patients, topical MSI-78 has been found to show equivalence to oral ofloxacin against polymicrobic diabetic foot ulcers. However, it should be mentioned that oral antibiotics work poorly against such infections because of poor perfusion, so this comparison may be inappropriate. Indeed, a Food and Drug Administration panel recently rejected this drug. A previous phase III study of MSI-78 (called Cytolex in that study) against impetigo failed because of a very large placebo effect associated with merely washing the infected site. Both nisin (a lantibiotic cationic peptide produced by AMBI, Purchase, N.Y.) and IB-367 (a protegrin-like cationic peptide from Intrabiotics, Mountain View, Calif.) have undergone phase I (safety) clinical trials successfully. They are being considered for stomach ulcers due to Helicobacter pylori (nisin) and oral mucositis (IB-367), although other indications are being considered. Indeed, a phase I safety trial of aerosolized IB-367 has been initiated in healthy adults with the objective of using this peptide against chronic Pseudomonas aeruginosa lung infections in cystic fibrosis patients. Micrologix Biotech Inc. (Vancouver, Canada) recently entered two phase I clinical trials for catheter-associated infections and serious acne infections. Thus, there is a considerable drive to try to examine clinical situations in which the assets of antimicrobial peptides will be efficacious. However, it is very difficult to assess the success of such ventures due to a dearth of information currently available.| |
ACKNOWLEDGMENTS |
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R.E.W.H. is a Medical Research Council of Canada Distinguished Scientist and acknowledges the Canadian Bacterial Diseases Network and the Canadian Cystic Fibrosis Foundation for funding his own peptide research. D.S.C. thanks the Special Trustees of St. Thomas' Hospital for financial support.
D.S.C. thanks R. W. Evans and C. L. Joannou for technical assistance and helpful discussions.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of British Columbia, 300-6174 University Blvd., Vancouver, BC, Canada V6T 1Z3. Phone: (604) 822-3308. Fax: (604) 822-6041. E-mail: bob{at}cmdr.ubc.ca.
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REFERENCES |
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Top
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References
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Antimicrobial Agents and Chemotherapy, June 1999, p. 1317-1323, Vol. 43, No. 6
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