Current Medicinal Chemistry - Anti-Infective Agents - Volume 1, Issue 4, 2002

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 α-helical structure, those with β-sheet structure, those with mixed helical / β- 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.

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.

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 β-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 β-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.

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.

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.