Editorial [ Biosynthesis of Natural Products Applied to Drug Discovery Guest Editor: Sergey B. Zotchev ]

Natural products synthesized by a variety of micro- and macro-organisms are chemically very diverse, and represent a rich source for drug discovery. These compounds are often not required for growth and maintenance of the organisms producing them, but rather act as chemical weapons or signalling molecules, thereby providing a certain advantage. Whatever is the true biological function of a certain natural product, humans have tried for years to adapt these compounds as medicines to cure various diseases. However, we must be aware of the fact that these compounds have been evolved to serve the organism's own needs, and not to help us in our fight against diseases. It follows then, that in most cases, although displaying desired biological activity, a natural product might not possess drug-like properties required for their successful application in medicine. Such properties as solubility, absorption in the gastrointestinal tract, metabolic and aqueous stability, geno- and cardiotoxicity, pharmacokinetics and pharmacodynamics are all important for consideration of a drug candidate. Some of these properties may be improved by medicinal chemistry through synthesis of natural product analogues. This approach is rather fast and efficient, and can rapidly provide important data on structure-activity relationship. However, many natural products are very complex, and specific chemical modifications are difficult or impossible to achieve. The latter problem may be circumvented by the use of biosynthetic engineering, a relatively new trend that has been developing over the last 20 years in several laboratories. The pre-requisite for biosynthetic engineering of a natural product is molecular cloning of the entire gene set encoding the enzymes involved in its biosynthesis. Current knowledge on basic principles of natural product biosynthesis, along with access to powerful bioinformatics tools and databases allow to deduce complete biosynthetic pathways for many natural products. Once the biosynthetic route for a natural product is established, and genetic tools for manipulating the producing organism developed, it becomes possible to alter biosynthetic genes in a specific manner in order to afford predictable changes in the chemical structure of the compound. Coupled to the knowledge on structure-activity relationship, such biosynthetic engineering becomes a powerful tool for improvement of pharmacological properties of natural products. This issue of “Current Topics in Medicinal Chemistry” is dedicated to the topic “Biosynthesis of Natural Products Applied to Drug Discovery”. The reviews from the leading scientists in the field of biosynthetic engineering presented in this issue highlight recent advances in applying this technology to the process of drug development. The reviews focus on biosynthesis of anti-bacterial, anti-fungal and anti-cancer antibiotics produced by actinomycetes, soil-dwelling bacteria with an enormous potential for production of diverse biologically active compounds. The first review from Baltz summarizes recent developments in understanding and engineering of the biosynthetic pathways for anti-bacterial lipopeptide antibiotics. These compounds penetrate the bacterial cell wall, leading to formation of pores, loss of electrical membrane potential and inhibition of peptidoglycan synthesis. The review not only compares biosynthetic pathways for several lipopeptides, but also suggests how this combined knowledge can be used for biosynthetic engineering. In particular, generation of new analogues of the clinically important antibiotic daptomycin is described. Several approaches for obtaining new daptomycin analogues are highlighted: module exchange in non-ribosomal peptide synthetases involved in daptomycin biosynthesis, heterologous transcomplementation, chemoenzymatic synthesis, and combinatorial biosynthesis. These studies provided important information on structure-activity relationship of lipopeptides, and will be extremely valuable for rational engineering of improved daptomycin analogues. In the next review, Caffrey et al. discuss issues of biosynthetic engineering of polyene macrolides, antibiotics currently used as anti-fungal and anti-parasitic agents. Polyene macrolides act through formation of hydrophilic channels in sterol-containing membranes, leading to leakage of ions and small molecules. The use of these antibiotics have been limited by serious side effects, and multiple attempts on generation of less toxic semi-synthetic derivatives have so far failed to bring any new polyene macrolides on the market.