Natural compounds produced by microorganisms have greatly contributed to the improvement of human health. Actinomycete and fungal strains are known to produce various secondary metabolites in their culture broths. The Kitasato Ōmura-Drug Discovery Group has found over 500 new compounds from these microorganisms. The production strains have been preserved by a long-term preservation method as Kitasato Microbial Library (KML).

The physicochemical properties of compounds produced by the preserved strains and fresh isolates were analyzed, and compared with a database. Subsequently, predicted new compounds were purified from culture broths and their structures were determined by NMR and MS. 35 compounds have been discovered by this approach, called Physicochemical screening. A compound, designated iminimycin, containing an iminium ion was discovered from the culture broth of Streptomyces griseus OS-3601. This KML strain has been stored for a long time as a streptomycin producing strain. Named trehangelin was discovered from rare actinomycete Plolymorphospora rubra K07-0510 isolated from the roots of orchid collected from Iriomote Island, Japan. Trehangelin A, the main compound, binds angelic acids to the 3, 3’ positions of trehalose. It has been found that the compound showed cytoprotective effect and accumulation of procollagen type I C-peptide, and further research is currently in progress.

It is shown that microorganisms are an inexhaustible gold mine of new natural compounds.

Infectious diseases caused by antibiotic-resistant bacteria has greatly increased and brought a recent public health crisis worldwide. Therefore, it is requisite to develop new antibiotics with a novel pharmacophore or molecular target. In this review, chemistry and antimicrobial properties of new microbial metabolites, tumescenamide C, chlorocatechelins, and saccharothriolides, as pharmaceutical leads produced by actinomycetes such as Streptomyes sp. and the rare actinomycete Saccharothrix sp. are summarized. In addition, precursor-directed in situ synthesis (PDSS) to obtain new derivatives of microbial metabolites in one pot is also described.

Microorganisms have been used as producers of primary and secondary metabolites as exemplified by amino acids and antibiotics. For these purposes, microorganisms possessing desirable abilities have been traditionally screened. However, we are recently able to employ another approach utilizing (meta) genome databases. By comparative genomics, we revealed alternative pathways for menaquinone and peptidoglycan biosynthesis and developed new screening strategies for antibiotics specifically acting on pathogens possessing these new pathways. We have also been mining biosynthetic genes of secondary metabolites and characterized them in detail. In this review, I briefly summarize these results.

After analysis of gene cluster for avermectin (used as a group of antiparasitic agents in human and veterinary medicine) biosynthesis was completed, we got the chance to analyze the genome of avermectin-producing Streptomyces avermitilis. Species of the genus Streptomyces(order Actinomycetales) of major pharmaceutical interest because they synthesized a variety of bioactive secondary metabolites. The linear chromosome of S. avermitilis contains 9,025,608 bases and 7,574 potential open reading frames. Furthermore, more than thirty gene clusters related to secondary metabolite biosynthesis were identified, but almost gene clusters were cryptic state. Comparison with a couple of Streptomyces genomes revealed that an internal 6.5-Mb region in the S. avermitilis genome was highly conserved with respect to gene order and content, and contained all known essential genes, but the terminal regions in both ends were not conserved and preferentially contained nonessential genes, including genes concerning secondary metabolite biosynthesis. In consideration of the genome information, S. avermitilis was constructed as a versatile model host for heterologous expression of genes encoding secondary metabolite biosynthesis. More than forty of the entire biosynthetic gene clusters for secondary metabolites were successively cloned and introduced into an engineered versatile host of S. avermitilis SUKA (Special Use of Kitasato Actinomytales) series. The production of metabolites in some transformants containing exogenous biosynthetic gene clusters was higher than that of the original producers, and some cryptic biosynthetic gene clusters in the original producer were also expressed in an engineered host SUKA strains. By using our versatile host and bioinformatics of enzymes, many terpene synthases were discovered from bacterial origin and 13 previously unidentified cyclic sesquiterpenes and diterpenes were isolated. Our innovative system concerning an engineered host and a couple of useful vectors was applied to create a new technology for the derivatization of peptide products (ribosomally synthesized and modified by post-translationally) and polyketide compounds synthesized by type I modular polyketide synthases (PKSs). Heterologous expression of many constructs in an engineered host SUKA strain gave 35 designed prethioviridamide derivatives, along with several unprecedented analogues. Cytotoxicity assay revealed that several derivatives showed more potent activities than those of natural product. The strategy can become one of the potential ways to produce supreme unnatural products. Although intense studies have established various methodologies for protein engineering of type I modular PKSs, the accurate targeting of desired regions in the PKS gene is still challenging due to the high sequence similarity between its modules. We developed an innovative technique to edit a target region of the gene encoding type I modular PKS. Proof-of-concept experiments using rapamycin PKS as a template showed that heterologous expression of edited biosynthetic gene clusters produced almost all the desired derivatives. Our technique will provide a platform to generate rationally designed natural product derivatives for future drug development.

Despite the dramatic progress of cancer research, cancer is a major cause of death in Japan, and development of effective therapeutic drugs is still needed. In recent years, molecular targeted therapeutic drugs targeting genes involved in cancer onset have greatly contributed to cancer treatment. In developing this molecular targeted drug, how to search for new drug target molecules and how to efficiently obtain the lead compound becomes a problem. Natural products have made a great contribution to the development of pharmaceutical development so far, accounting for about 60% of medicines approved in the past 30 years. Meanwhile, in recent years, the mainstream of drug development has shifted to synthetic compounds, and natural product screening tends to shrink. However, natural products are overwhelmingly dominant in terms of “structural diversity” and “Bioactive diversity” compared to synthetic compounds, therefore, natural products still have sufficient potential as a drug seed. We therefore conducted natural product screening in microorganisms to obtain the compounds that function as antitumor drug-seed. In this article, we describe the studies on the antitumor drug-seed from the microbial secondary metabolites we isolated.