The Structural and Functional Diversity of Naturally Occurring Antimicrobial Peptides Pp-319-341
K. Johan
Rosengren, Ailsa M. McManus and David J. Craik
Anti-infective Agents Produced by the Hyphomycetes Genera Trichoderma and Gliocladium Pp-343-374
E.L.
Ghisalberti
Industrial Synthesis of Semi-Synthetic b-Lactam Antibiotics: Recent Developments in Enzyme Biocatalysis for Improved and MORE Sustainable Processes Pp-375-387
Roberto
Fernandez-Lafuente, Cesar Mateo, Olga Abian, Gloria Fernandez-Lorente, Jose M.
Palomo, Manuel Fuentes and Jose M. Guisán
Heterocyclic Nucleosides. Chemical Synthesis and Biological Properties Pp-389-411
Pedro
Merino
Antimicrobial Peptides as Novel Therapeutic Agents to Combat Drug-Resistant Microbial Infections Pp-413-430
N.
Sitaram and R. Nagaraj
[Back to top] The Structural and Functional Diversity of Naturally Occurring Antimicrobial Peptides
K. Johan
Rosengren, Ailsa M. McManus and David J. Craik
Antimicrobial peptides
occur in a diverse range of organisms from microorganisms to insects, plants
and animals. Although they all have the common function of inhibiting or
killing invading microorganisms they achieve this function using an extremely
diverse range of structural motifs. Their sizes range from approximately 10-90
amino acids. Most carry an overall positive charge, reflecting a preferred mode
of electrostatic interaction with negatively charged microbial membranes. This
article describes the structural diversity of a representative set of
antimicrobial peptides divided into five structural classes: those with a-helical structure, those with
b-sheet structure, those with mixed helical/b-
sheet structure, those with irregular structure, and those incorporating a
macrocyclic structure. There is a significant diversity in both the size and
charge of molecules within each of these classes and between the classes. The
common feature of their three-dimensional structures is, however, that they
have a degree of amphipathic character in which there is separate localisation
of hydrophobic regions and positively charged regions. An emerging trend amongst
antimicrobial proteins is the discovery of more macrocyclic analogues.
Cyclisation appears to impart an additional degree of stability on these
molecules and minimizes proteolytic cleavage. In conclusion, there appear to be
a number of promising opportunities for the development of novel clinically
useful antimicrobial peptides based on knowledge of the structures of naturally
occurring antimicrobial molecules.
[Back to top] Anti-infective Agents Produced by the Hyphomycetes Genera Trichoderma and Gliocladium
E.L.
Ghisalberti
Trichoderma and
Gliocladium species are common hyphomycetes that occur in all climate zones,
ranging from Antarctica to the tropics, and are ubiquitous in the environment,
especially in soils. Although they are aggressive competitors in the soil, most
species are non-phytopathogenic and, generally, do not affect healthy humans.
Their ability to express high cellulase activity has been commercially
exploited. Chitinolytic enzymes produced by these fungi are thought to be
responsible for the degradation of cell walls of those fungal plant pathogens
which they parasitise. Trichoderma and Gliocladium species have long been studied
as biological control agents of phytopathogens and are characterised by their
ability to produce a wide range of secondary metabolites with diverse
biological actions, including antifungal activity. The secondary metabolism of
the two genera is dominated by compounds derived from the polyketide pathway
and from elaboration of amino acid metabolism, but sesquiterpenes and
sterol-derived metabolites are also represented. In this review, the potential
of these fungi as producers of secondary metabolites that show antibacterial
and antifungal activity is considered. Various aspects of the chemistry,
biosynthesis and bioactivity of these compounds is discussed and their
relationship to other recognised antiinfective metabolites is emphasised.
[Back to top] Industrial Synthesis of Semi-Synthetic b-Lactam Antibiotics: Recent Developments in Enzyme Biocatalysis for Improved and MORE Sustainable Processes
Roberto
Fernandez-Lafuente, Cesar Mateo, Olga Abian, Gloria Fernandez-Lorente, Jose M.
Palomo, Manuel Fuentes and Jose M. Guisán
The production, under environmentally benign conditions, of efficient and more cost-effective anti-infective agents (available to the whole mankind) is one of most exciting dreams of the industrial medicinal chemistry.
Semi-synthetic b-lactam antibiotics are very effective anti-infective agents. They are very stable and be can be used via oral delivering. They exhibit a very wide spectrum of anti-bacterial activity and minimal side-effects after being massively used for a very long time. In this way, we can assume that semi-synthetic b-lactam antibiotics are going to continue to be one of the key anti-infective agents for the next years.
The condensation of natural or modified antibiotic nuclei with different acyl donor chains is one of the key steps for the industrial synthesis of these anti-infective agents. Up to now, these condensations are mainly carried out through classical chemical methods and it implies a number of economical, ecological and technological drawbacks (high energy requirements, many protection and deprotection steps, utilization of toxic methylene chloride as solvent, etc). Enzyme biocatalysts may be very useful to catalyze these selective condensations under very mild experimental and environmental conditions. In fact, the possibility to use enzymes to carry out such biotransformations, at laboratory scale, has been discussed and demonstrated a long time ago. However, industrial synthesis of beta-lactam antibiotic is still carried out via unfavorable chemical routes. In fact, enzymes have been not designed by nature to act in industrial reactors: they are usually very unstable, inhibited by substrates and products and they may have not ideal catalytic properties for industrial uses (high reaction rates, required selectivity, ability to reach quantitative synthetic yields, stability enough to run a number of reaction cycles, etc). These limitations of enzyme biocatalysis become even more significant mainly when the enzyme is going to be used with non-natural substrates, catalyzing non-natural processes and working under non conventional conditions.
However, in the last
ten years, a number of papers have reported substantial improvement of these
enzymatic synthetic approaches (new enzymes, better enzyme derivatives,
improved reaction designs and so on) and it seems that the massive industrial
implementation of enzymes in antibiotic synthesis is very close. In these
review, we would like to make a critical discussion of these very interesting
advances in the application of enzyme biocatalyst for the industrial synthesis
of semi-synthetic antibiotics.
[Back to top] Heterocyclic Nucleosides. Chemical Synthesis and Biological Properties
Pedro
Merino
A revision of the most
recent advances on chemistry and biological activity of nucleoside analogues in
which the furanose ring has been replaced by a different heterocyclic ring
(heterocyclic nucleosides) is summarized. Encouraging results obtained by
lamivudine, the flagship of that family of nucleoside analogues, has created
great interest and focused attention on that sort of compounds. As a
consequence, the synthesis of new generations of heterocyclic nucleosides
flourished in hope of new drug discovery with improved pharmacokinetic
properties. This review outlines essentially the recent progress in chemical
methods directed to the preparation of the title compounds.
[Back to top] Antimicrobial Peptides as Novel Therapeutic Agents to Combat Drug-Resistant Microbial Infections
N.
Sitaram and R. Nagaraj
The discovery of penicillin and the tremendous success achieved in preventing fatalities due to microbial infections by using it as a therapeutic antibiotic was perhaps the starting point of systematic investigations on the research and application of therapeutic antibiotics. Over the years, a large number of natural semi-synthetic and synthetic antibiotics have been used to successfully treat infections caused by a broad range of microorganisms, especially bacteria. The mechanisms of action of therapeutically used antibiotics have been worked out and almost all of them interfere with some aspect of bacterial metabolism. The initial success in the effective use of antibiotics and the under-estimation of the ability of bacteria to overcome the effect of antibiotics has led to the serious problem of resistance to several of the therapeutically used antibiotics. The seriousness of the problem in clinical medicine has been the focus of attention in recent years. The problem was also necessitated the search for molecules that would be more refractory to the development of resistance.
Now, innate immunity in species across the evolutionary scale from
insects to mammals is mediated by peptides that exert their activities by
permeabilizing bacterial membranes. Although the primary and secondary
structures of these hostdefense peptides vary considerably, their common
mechanism of action would suggest that there could be an evolutionary advantage
in them to counter bacteria and resistance may not develop against them. In
this review, we examine various facets of host-defense antibacterial peptides
with a view to explore their potential as anti-infective agents.