Future Trends In Biofungicide Research

During the last two decades, there were numerous efforts focusing on the isolation and identification of a wide range of biologically active natural products. As a result, hundreds of thousands to millions of compounds became available for the evaluation of their value as potential lead compounds. The concept of a HTS was developed to screen a large number of chemical libraries, which overcome the limitation of conventional in vitro and in vivo assay. The HTS is made possible by the advance in assay system, which was designed to target a specific biochemical event in fungal metabolism. A direct measure of the activity of the compound at the target of interest can be done without complications arising from other metabolic events. These approaches can enhance the possibility to discover new and useful biofungicides by supplying unique bioassay system. This innovative procedure was already applied in developing new fungicides such as sordarins mentioned earlier. The target-directed screening will be fortified by DNA sequence information that is exponentially increased in recent years by a number of fungal genome projects. The genomic information can provide a wealth of new targets to be validated and screened for new antifungal leads (DiDomenico 1999).

Along with the innovations in screening systems, the efforts to diversify the chemical library of microbial metabolites has been continued through combinatorial approaches. Recently, the ability to synthesize a large number of chemical libraries from core structure of antibiotics was greatly enhanced by the advance of rapid combinatorial/ parallel synthesis method (Caporale 1995). The diversity and numbers of distinct compounds in combinatorial library enhance the possibility of finding a chemical structure with the desired properties. Combinatorial libraries can be synthesized in many different ways as reviewed by Dolle (1999). However, most of the successes in combinatorial chemistry have been accomplished by using small libraries to improve the properties of a specific toxophore. The successful optimization of azole and oxazolidinone lead compounds suggested a promising future of combinatorial chemistry in biofungicide research (Trias 2001).

As another approach to diversify the chemical library of microbial metabolites, combinatorial biosynthesis was proposed to generate "unnatural" natural products, which use genetic information and DNA recombination techniques to alter the biosynthetic pathway of the microorganism to produce the designed chemical structure. This can also be done by introducing hybrid enzyme or/and swapping with heterologous biosynthetic machinery involved in the synthesis of other antibiotics (Cropp et al. 2002; Reynolds 1998). More recently, previously unknown chemical structures were generated by interchanging enzyme subunits or making hybrid enzymes of type I polyketide synthases (PKSs) (Kim et al. 2002; McDaniel et al. 1999; Yoon et al. 2002). Most of the combinatorial biosynthesis researches have been done on PKSs, especially in Streptomyces. Recently, the biosynthetic gene clusters of antifungal antibiotic pyoluteorin and 2,4-diacetylphloroglucinol also were identified from plant-associated pseudomonads, the well-known biological control agents (Bender et al. 1999). These biosynthetic gene clusters are expected to be used for the template of combinatorial biosynthesis for biofungicide development, although a number of questions about their enzymological functions still remains to be elucidated.

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