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Current
Pharmaceutical Biotechnology
ISSN: 1389-2010
Current Pharmaceutical Biotechnology
Volume 10, Number 1, January 2009
Contents
Antimicrobial Substances Produced by Bacteria, Marine
Sponges, and Tropical Plants
Guest Editor: Maria do Carmo de Freire Bastos
Editorial Pp. 1
M.C.F. Bastos
[PMID:
19149586 PubMed - indexed for MEDLINE]
Lantibiotics: Mode of Action, Biosynthesis and Bioengineering
Pp. 2-18
G. Bierbaum and H.-G. Sahl
[Abstract]
[Purchase
Article] [PMID:
19149587 PubMed - indexed for MEDLINE]
Structure-Function Relationships of the
Non-Lanthionine Containing Peptide (Class II) Bacteriocins
Produced by Gram-Positive Bacteria Pp. 19-37
J. Nissen-Meyer, P. Rogne, C. Oppegård,
H.S. Haugen and P.E. Kristiansen
[Abstract]
[Purchase
Article][PMID:
19149588 PubMed - indexed for MEDLINE]
Staphylococcal Antimicrobial Peptides:
Relevant Properties and Potential Biotechnological Applications
Pp. 38-61
M.C.F. Bastos, H. Ceotto, M.L.V. Coelho
and J.S. Nascimento
[Abstract]
[Purchase
Article][PMID:
19149589 PubMed - indexed for MEDLINE]
Use of Lactobacilli and their Pheromone-Based
Regulatory Mechanism in Gene Expression and Drug Delivery
Pp. 62-73
D.B. Diep, G. Mathiesen, V.G. H. Eijsink
and I.F. Nes
[Abstract]
[Purchase
Article] [PMID:
19149590 PubMed - indexed for MEDLINE]
Antibacterial and Antitumorigenic Properties
of Microcin E492, a Pore-Forming Bacteriocin Pp.
74-85
R. Lagos, M. Tello, G. Mercado, V. García
and O. Monasterio
[Abstract]
[Purchase
Article] [PMID:
19149591 PubMed - indexed for MEDLINE]
Marine Sponges: Potential Sources of
New Antimicrobial Drugs Pp. 86-105
M.S. Laport, O.C.S. Santos and G.
Muricy
[Abstract]
[Purchase
Article] [PMID:
19149592 PubMed - indexed for MEDLINE]
Plant Extracts: Search for New Alternatives
to Treat Microbial Diseases Pp. 106-121
D.S. Alviano and C.S. Alviano
[Abstract]
[Purchase
Article] [PMID:
19149593 PubMed - indexed for MEDLINE]
General Article
Advances in Peptide Pharmaceuticals Pp. 122-137
Cynthia L. Stevenson
[Abstract]
[Purchase
Article] [PMID:
19149594 PubMed - indexed for MEDLINE]
Research Article
The Hydroxyl-Modified Surfaces on Glass Support for Fabrication
of Carbohydrate Microarrays Pp. 138-146
Gang Nan, Hua Yan, Ganglong Yang, Qiang
Jian, Chao Chen and Zheng Li
[Abstract]
[Purchase
Article] [PMID:
19149595 PubMed - indexed for MEDLINE]
Abstracts
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[PMID:
19149586 PubMed - indexed for MEDLINE]
Editorial:
The spread of microbial resistance leads to a growing
demand for novel antimicrobial drugs. However, despite the
significant efforts in academia and the pharmaceutical industry,
no genuinely new class of antimicrobial compounds has reached
the market in the last years. However, a large variety of
substances with potential antimicrobial activity is widely
distributed in nature being produced by both prokaryotes and
eukaryotes. Therefore, in this special issue of Current Pharmaceutical
Biotechnology, we attempt to provide the reader with an overview
on antimicrobial substances produced by bacteria, marine sponges,
and tropical plants. Concerning prokaryotes, the reviews will
focus on bacteriocins, antimicrobial peptides produced by
bacteria.
Bierbaum and co-workers focus their review on the current
developments in the lantibiotic (class I bacteriocins) field
and on recent findings concerning mode of action, biosynthesis
and engineering of lantibiotics produced by Gram-positive
bacteria, while the review written by Nissen-Meyer and co-workers
focuses on the structure and mode of action of class II bacteriocins.
Structure-function analysis of bacteriocins is particularly
relevant for illuminating how these potent bactericidal agents
function at a molecular level. Such knowledge is fundamental
when considering the rational design of new bacteriocin variants
with improved properties that make them especially useful
for medical and biotechnological applications.
Bastos and co-workers describe the relevant features of staphylococcins,
bacteriocins produced by staphylococci, discussing examples
of their potential biotechnological applications mainly as
antibacterial agents.
Diep and co-workers discuss some well-characterised quorum
sensing networks involved in regulation of bacteriocin production
in lactobacilli, with special focus on the use of the regulatory
components in gene expression and on lactobacilli as potential
delivery vehicle for therapeutic and vaccine purposes.
The review of Lagos and co-workers is focused on microcin
E492 features, a bacteriocin that, besides an antimicrobial
activity, also displays a cytotoxic effect on tumor cell lines
involving apoptosis induction. This trait makes this bacteriocin
also suitable for cancer treatment.
Laport and co-workers describe an overwhelming number of bioactive
substances that have been discovered in sponges and their
associated microorganisms. Sponges are considered the most
prolific marine producers of novel substances exhibiting antimicrobial
activity with a variety of biotechnologically relevant properties.
Finally, the main focus of the review written by Alviano and
Alviano are the antimicrobial and antioxidant properties of
bioactive compounds obtained from crude plant extracts and
essential oils of Brazilian plants used empirically in folk
medicine to treat various infectious disorders.
From the data presented in these reviews, we can realize that
considerable research to date has led to the identification
of a growing number of antimicrobial substances that may provide
valuable addition to the current range of antimicrobial compounds
available for animal and human medicine. However, we should
keep in mind that, although substantial progress has been
made in identifying novel drug leads from a variety of living
organisms, great efforts are still need to advance to their
clinical applications. Therefore, I hope that this special
issue of Current Pharmaceutical Biotechnology can be useful
to those readers already working on antimicrobial substances,
stimulating discussion and further studies, but principally
serving to attract new researchers from other fields interested
in exploitation of the biotechnological applications of these
substances.
Maria do Carmo de Freire Bastos
Guest Editor
Departamento de Microbiologia Geral
Instituto de Microbiologia Prof. Paulo de Góes
Universidade Federal do Rio de Janeiro
21941-590, Rio de Janeiro
Brasil
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Article] [PMID:
19149587 PubMed - indexed for MEDLINE]
Lantibiotics: Mode of Action, Biosynthesis and Bioengineering
G. Bierbaum and H.-G. Sahl
Lantibiotics are gene-encoded peptides that contain intramolecular
ring structures, introduced through the thioether containing
lanthionine and methyllanthionine residues. The overwhelming
majority of the lantibiotics shows antibacterial activity.
Some lantibiotics, e. g. nisin, are characterized by a dual
mode of action. These peptides form a complex with the ultimate
cell wall precursor lipid II, thereby inhibiting cell wall
biosynthesis. The complexes then aggregate, incorporate further
peptides and form a pore in the bacterial membrane. Recent
results show that complexing of lipid II is widespread among
lantibiotics; however, pore formation depends on the overall
length of the peptide and the lipid composition of the test
strain membrane. In the two-component system of lacticin 3147,
the two functions are performed by the two different peptides.
The genetic information for production of lantibiotics is
organized in gene clusters which contain a structural gene
(lanA) for the lantibiotic prepeptide. The modifications
are introduced by one biosynthetic enzyme (LanM) or a combination
of a dehydratase (LanB) and a cyclase (LanC). These enzymes
have been in the focus of recent bioengi-neering studies:
The structure of NisC has been resolved, the reaction mechanism
of LctM was elucidated and the active site residues were characterized
by mutagenesis studies. In vitro modification systems
have successfully been used to introduce thioether rings into
other biologically active peptides. Furthermore, variant lantibiotics
with enhanced properties have been engineered and at least
one promising new lantibiotic with strong activity against
multiresistant pathogens has been described.
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[Purchase
Article] [PMID:
19149588 PubMed - indexed for MEDLINE]
Structure-Function Relationships of the Non-Lanthionine Containing
Peptide (Class II) Bacteriocins Produced by Gram-Positive
Bacteria
J. Nissen-Meyer, P. Rogne, C. Oppegård,
H.S. Haugen and P.E. Kristiansen
This review focuses on the structure and mode-of-action
of non-lanthionine-containing peptide bacteriocins produced
by Gram-positive bacteria. These bacteriocins may be divided
into four groups: (i) the anti-listerial one-peptide pediocin-like
bacteriocins that have very similar amino acid sequences,
(ii) the two-peptide bacteriocins that consist of two different
peptides, (iii) the cyclic bacteriocins, and (iv) the linear
non-pediocin-like one-peptide bacteriocins. These bacteriocins
are largely cationic, contain 20 to 70 residues, and kill
cells through membrane-permeabilization. The pediocin-like
bacteriocins are the ones that are best characterized. Upon
contact with target membranes, their cationic N-terminal half
forms a β-sheet-like
structure that binds to the target cell surface, while their
more hydrophobic helical-containing C-terminal half penetrates
into the hydrophobic core of target-cell membranes and apparently
binds to the mannose phosphotransferase permease in a manner
that results in membrane leakage. Immunity proteins that protect
cells from being killed by pediocin-like bacteriocins bind
to the bacteriocin-permease complex and prevent bacteriocin-induced
membrane-leakage. Recent structural analyses of two-peptide
bacteriocins indicate that they form a helix-helix structure
that penetrates into cell membranes. Also these bacteriocins
may act by binding to integrated membrane proteins. It is
proposed that many membrane-active peptide bacteriocins kill
target-cells through basically the same mechanism; the common
theme being that a membrane-penetrating part of bacteriocins
bind to a membrane embedded region of an integrated membrane
protein, thereby causing conformational alterations in the
protein that in turn lead to membrane-leakage and cell death.
[Back to top] [Purchase
Article] [PMID:
19149589 PubMed - indexed for MEDLINE]
Staphylococcal Antimicrobial Peptides: Relevant Properties
and Potential Biotechnological Applications
M.C.F. Bastos, H. Ceotto, M.L.V. Coelho
and J.S. Nascimento
Bacteriocins are bacterial antimicrobial peptides with
bactericidal activity against other bacteria. Staphylococcins
are bacteriocins produced by staphylococci, which are Gram-positive
bacteria with medical and veterinary importance. Most bacteriocins
produced by staphylococci are either lantibiotics (e.g., Pep5,
epidermin, epilancin K7, epicidin 280, staphylococcin C55/BacR1,
and nukacin ISK-1) or class II bacteriocins (e.g., aureocins
A70 and 53). Only one staphylococcin belonging to class III,
lysostaphin, has been described so far. Production of staphylococcins
is a self-protection mechanism that helps staphylococci to
survive in their natural habitats. However, since these substances
gener-ally have a broad spectrum of activity, inhibiting several
human and animal pathogens, they have potential biotechnological
applications either as food preservatives or therapeutic agents.
Due to the increasing consumer awareness of the risks derived
not only from food-borne pathogens, but also from the artificial
chemical preservatives used to control them, the interest
in the discovery of natural food preservatives has increased
considerably. The emergence and dissemination of antibiotic
resistance among human and animal pathogens and their association
with the use of antibiotics constitute a serious problem worldwide
requiring effective measures for controlling their spread.
Staphylococcins may be used, solely or in combination with
other chemical agents, to avoid food contamination or spoilage
and to prevent or treat bacterial infectious diseases. The
use of combinations of antimicrobials is common in the clinical
setting and expands the spectrum of organisms that can be
targeted, prevents the emergence of resistant organisms, decreases
toxicity by allowing lower doses of both agents and can result
in synergistic inhibition.
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[Purchase
Article] [PMID:
19149590 PubMed - indexed for MEDLINE]
Use of Lactobacilli and their Pheromone-Based Regulatory Mechanism
in Gene Expression and Drug Delivery
D.B. Diep, G. Mathiesen, V.G. H. Eijsink
and I.F. Nes
Lactobacilli are common microorganisms in diverse vegetables
and meat products and several of these are also indigenous
inhabitants in the gastro-intestinal (GI) tract of humans
and animals where they are believed to have health promoting
effects on the host. One of the highly appreciated probiotic
effects is their ability to inhibit the growth of pathogens
by producing antimicrobial peptides, so-called bacteriocins.
Production of some bacteriocins has been shown to be strictly
regulated through a quorum-sensing based mechanism mediated
by a secreted peptide-pheromone (also called induction peptide;
IP), a membrane-located sensor (histidine protein kinase;
HPK) and a cytoplasmic response regulator (RR). The interaction
between an IP and its sensor, which is highly specific, leads
to activation of the cognate RR which in turn binds to regulated
promoters and activates gene expression. The HPKs and RRs
are built up by conserved modules, and the signalling between
them within a network is efficient and directional, and can
easily be activated by exogenously added synthetic IPs. Consequently,
components from such regulatory networks have successfully
been exploited in construction of a number of inducible gene
expression systems. In this review, we discuss some well-characterised
quorum sensing networks involved in bacteriocin production
in lactobacilli, with special focus on the use of the regulatory
components in gene expression and on lactobacilli as potential
delivery vehicle for therapeutic and vaccine purposes.
[Back to top]
[Purchase
Article] [PMID:
19149591 PubMed - indexed for MEDLINE]
Antibacterial and Antitumorigenic Properties of Microcin E492,
a Pore-Forming Bacteriocin
R. Lagos, M. Tello, G. Mercado, V. García
and O. Monasterio
Microcins are a family of low-molecular weight bacteriocins
produced and secreted by Gram-negative bacteria. This review
is focused on microcin E492, a pore-forming bacteriocin produced
by Klebsiella pneumoniae RYC492 that exerts its antibacterial
action on related strains. The steps necessary for the production
of active microcin E492 involve post-translational modification
with a catechol-type siderophore at the C-terminal
and proteolytic processing during export to the extracellular
space. This bacteriocin has a modular structure, with a toxic
domain at the N-terminal and an uptake domain at
the C-terminal of the mature protein. The mechanism
by which the C-terminal of microcin E492 is recognized
by catecholate siderophore receptors is called the “Trojan
horse” strategy, because the C-terminal structure
mimics essential bacterial elements, which are recognized
by the respective receptors and translocated across the outer
membrane to exert antibacterial action. The C-terminal
uptake module can be exchanged and used with other toxic domains.
Microcin E492 also has a cytotoxic effect on malignant human
cell lines. The cytotoxic mechanism is through apoptosis,
a desired mechanism for cancer therapy. The ability of microcin
E492 to form amyloid-like fibrils constitutes a property that
can be exploited in the formulation of this bacteriocin as
an antitumoral agent, because these fibrils can behave as
stable depots to ensure the sustained release of a biologically
active molecule. Alternatively, live bacteria can be used
as a continuous source of microcin E492 production in specific
tumors.
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[Purchase
Article] [PMID:
19149592 PubMed - indexed for MEDLINE]
Marine Sponges: Potential Sources of New Antimicrobial Drugs
M.S. Laport, O.C.S. Santos and G.
Muricy
Sponges (phylum Porifera) are sessile marine filter feeders
that have developed efficient defense mechanisms against foreign
attackers such as viruses, bacteria, or eukaryotic organisms.
Marine sponges are among the richest sources of pharmacologically-active
chemicals from marine organisms. It is suggested that (at
least) some of the bioactive secondary metabolites isolated
from sponges are produced by functional enzyme clusters, which
originated from the sponges and their associated microorganisms.
More than 5,300 different products are known from sponges
and their associated microorganisms, and more than 200 new
metabolites from sponges are reported each year. As infectious
microorganisms evolve and develop resistance to existing pharmaceuticals,
the marine sponge provides novel leads against bacterial,
viral, fungal and parasitic diseases. Many marine natural
products have successfully advanced to the late stages of
clinical trials, as for example ara-A (vidarabine), an anti-viral
drug used against the herpes simplex encephalitis virus. This
substance is in clinical use for many years. Moreover, a growing
number of candidates have been selected as promising leads
for extended preclinical assessment, including manzamine A
(activity against malaria, tuberculosis, HIV, and others),
lasono-lides (antifungal activity) and psammaplin A (antibacterial
activity). In this review we have surveyed the discoveries
of products derived from marine sponges and associated bacteria
that have shown in vivo efficacy or potent in
vitro activity against infectious and parasitic diseases,
including bacterial, viral, fungal and protozoan infections.
Our objective was to highlight the susbtances that have the
greatest potential to lead to clinically useful treatments.
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[Purchase
Article] [PMID:
19149593 PubMed - indexed for MEDLINE]
Plant Extracts: Search for New Alternatives
to Treat Microbial Diseases
D.S. Alviano and C.S. Alviano
Medicinal plants constitute the base of health care systems
in many societies. The recovery of the knowledge and practices
associated with these plant resources are part of an important
strategy linked to the conservation of biodiversity, discovery
of new medicines, and the bettering of the quality of life
of poor rural communities. Research in phytosciences, an emerging
multidisciplinary science, is almost unlimited, with several
aspects to be discussed. Therefore, the focus of the present
review is mainly on the antimicrobial and antioxidant properties
of bioactive phytocompounds resultant of our research with
crude plant extracts and essential oils of medicinal plants
belonging to different families, used in various infectious
disorders. The results obtained in the last years warrant
the present review, discussing not only the use of several
medicinal plants against bacteria, yeast, filamentous fungi
and protozoa, but also their mechanisms of action, interactions
with macromolecules and potential for toxicity in mammalian
cells. Problems related to the efficacy of the isolation techniques
and stability of bioactive compounds are also commented on.
In addition, this review aims to emphasize the greatest importance
to investigate plant species that have not been the subject
of pharmacological studies, although their popular uses have
been reported.
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19149594 PubMed - indexed for MEDLINE]
Advances in Peptide Pharmaceuticals
Cynthia L. Stevenson
Drug delivery strategies for peptide pharmaceuticals
have incorporated a wide range of structure activity relationships,
analog generation to impart protease resistance and increased
bioavailability, novel formulations, and delivery systems
to target optimal therapeutic dosing requirements. Advances
in peptide pharmaceuticals have provided products for the
treatment of diabetes, obesity, Crohn’s disease, osteoporosis,
cancer, cardiovascular disease, immunotherapy, acromegaly,
enuresis, pain, and antimicrobials. Here we review these marketed
peptides and new peptidomimetic therapies currently in clinical
trials.
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19149595 PubMed - indexed for MEDLINE]
The Hydroxyl-Modified Surfaces on Glass Support for Fabrication
of Carbohydrate Microarrays
Gang Nan, Hua Yan, Ganglong Yang, Qiang
Jian, Chao Chen and Zheng Li
Glycan-protein interactions play important biological
roles in biological processes. But there is a lack of simple
high-throughput methods to elucidate recognition events between
carbohydrates and protein. Although, there have been a number
of glycan arrays developed in recent years utilizing different
strategies and for different purposes, the method presented
in this paper, a direct covalent immobilization of sugars
to hydroxyl-modified glass surface, can be a very useful general
method. Here, two strategies have been developed for the production
of carbohydrate microarrays by the underivatized sugars that
efficiently immobilized on hydroxyl-functionalized glass surface
by formation of glycosidic bond with the hemiacetal group
at the reducing end of the suitable carbohydrates via condensation.
Firstly, untreated glass slides were amino- and epoxy-silanized,
respectively. Then, they were further hydroxyl functionalized
with different surface chemistries. The carbohydrate microarrays
were fabricated on hydroxyl-functionalized glass by robotic
arrayer. Additionally, experiments for the characterization
of carbohydrates-protein interaction were performed to compare
these strategies. Overall best results in terms of conveniency
and sensitivity were obtained with hydroxyl-functionalization
on epoxysilanized surfaces. The hydroxyl-functionalized slide
was used to detect the amount of mannose immobilized on the
glass surface. The limit of detection of the fabricated mannose
microarray was 100 nM.
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