Antibiotics Laboratory

Outline

Small molecules produced by microorganisms have diversity in chemical structures and biological activities. Our laboratory is focusing on the isolation of new compounds that regulate mammalian cell function from microbial metabolites. Cellular factors involved in proliferation, differentiation and apoptosis in mammalian cells are molecular targets to be inhibited by chemical compounds. The compounds isolated from microorganisms are deposited in the newly established RIKEN Natural Products Depository (NPDepo), which assembles chemical libraries. Our laboratory is also devoted to the cloning of biosynthetic gene clusters of microbial secondary metabolites, the investigation of the molecular interaction between small molecules and their binding proteins, and proteomic analyses of drug targets. This research will provide the biochemical tools to investigate the complex biochemical processes of mammalian cell functions and also establish a foundation for developing new medicines such as antitumor agents.

Recent Research Topic

Elucidation of biological systems by chemical power

Fig. 1 Bioprobes discovered in our laboratory

Based on long standing antibiotics research, we now pay much attention to developing pharmaceutical agents and marketing biochemical reagents, and we have succeeded in commercializing compounds discovered in our laboratory as biochemical reagents (Fig. 1). Since microbial metabolites are expected to show interesting biological activities, the cloning of biosynthetic gene clusters which enable us to produce desired compounds is underway. As a part of that effort, we accumulate microbial metabolites and construct chemical libraries for the screening of new bioactive compounds. In this context, we are constructing the RIKEN Natural Products Depository (NPDepo) where we accumulate compounds isolated not only by us but synthesized or isolated by others. These compounds can be used by any researcher for drug screening.

It is also important to develop high-throughput screening systems to exploit the biological activities of chemical compounds. The chemical microarray is one of the most powerful platforms. We are carrying out the screening of chemical inhibitors that affect key enzymes required for proliferation, differentiation, and apoptosis in tumor cells. We are also identifying the molecular targets of newly isolated compounds by utilizing a proteomics method, 2-dimensional fluorescence differential gel electrophoresis and/or by using affinity beads linked with specific bioprobes (Fig. 2). Some bioprobes such as reveromycin A (Fig. 3) and epolactaene were discovered through cell-based screening. Contrarily, RK-682 and RKTS-33 were discovered by more target-oriented screening systems. Since they can be used for the investigation of complex biochemical processes of mammalian cell functions, we call these compounds bioprobes. Bioprobes are not only tools for chemical biology but also candidates for new antitumor agents.

Among the progress of molecular biological technologies, RNAi technology enables us to elucidate protein function in complex biological systems. Chemical biology uses bioprobes instead of gene mutation or RNAi to control protein function rapidly and conditionally just by adding or washing out the bioprobes.

Recently, many pharmaceutical companies have shifted their effort from natural product screening to combinatorial chemistry for high-throughput screening. Natural product screening is thought to be a slow and costly strategy to discover lead candidates, and combinatorial chemistry is thought to be a more rapid and attractive approach. However, natural products, especially microbial metabolites are like a treasure chest, containing interesting lead compounds with novel structures and useful biological activities. Moreover, chemical biology is a fascinating new field, which is based on new bioprobes.

Fig. 2 How bioprobes are used in chemical biology

Fig. 3 Target molecules of osteoclasts-targeting compounds