Bioactive fungal natural products through classic and biocombinatorial approaches

Abstract

The kingdom of fungi is an important source of bioactive natural products, which have been a driving force in the development of modern pharmaceutical industry. Fungal natural products have provided revolutionary pharmaceuticals against various diseases, and have provided unique and inspirational chemicals for innovative drugs. Fungi are essentially an untapped source of drugs in spite of many remarkable therapeutic agents discovered from them so far. Of approximately 1.5 million species of fungi, to date only about 70,000 species have been described. Among these 70,000 species, only a small fraction can be isolated from nature and fermented in laboratory media for drug screening. The vast majority of slow-growing and unculturable fungi have received little attention for drug discovery due to technical limitations. Therefore, the potential for discovering bioactive agents from slow-growing and unculturable fungi is even greater than that from the species that we have explored. With the maturing technology of genetic engineering, it is now possible to express genes from unculturable organisms in laboratory strains for secondary metabolism study. Today, mankind is not only still facing the challenge to treat untamed diseases, but is also fighting newly recognized diseases, and diseases that once were subdued but are developing resistance to the current therapeutic regimes. In this review, we will discuss recent developments and progress of several important fungal metabolites and their derived products as examples of drugs produced by natural isolates. We will also discuss the current progress of biocombinatorial drug discovery by genetic engineering approaches, as well as possibilities and strategies of exploring genetic diversity from unculturable fungi for drug discovery. The vast fungal kingdom, which consists of an estimated 1.5 million species, is of interest to the pharmaceutical industry for its production of many important secondary metabolites. Since more than one half century ago, when the fungal metabolite penicillin was first partially purified and used for treating bacterial infections, bioactive fungal metabolites have strongly influenced the development of the modern pharmaceutical industry. Mevinolin, cyclosporin A, and β-lactam antibiotics are examples of revolutionary pharmaceuticals that have a fungal origin. In addition, the diverse and unique chemical structures of fungal metabolites have served as an important source of inspiration for structural motifs to synthetic chemists [1–2]. Fungal metabolites of various biosynthetic origins have produced breakthrough pharmaceutical and agricultural products during the last decade. In this review, we describe recent progress of several fungal metabolites of pharmaceutical and agricultural importance. This by no means includes all the structures, rather we aim to demonstrate the potential of discovering new chemical structures from fungal sources and the value of fungi as an important source of compounds. Readers are encouraged to study recent reviews and databases that have extensively covered fungal natural products [3–5, 133]. In spite of the remarkable therapeutic agents discovered so far, fungi are essentially an untapped source of active metabolites. Only a small fraction of the fungal taxa can be and have been fermented in laboratory media for drug discovery. In this chapter, we also briefly discuss the potential of using biocombinatorial approaches to tap into the genetic diversity of fungi for drug discovery.