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Discovery of Novel Bioactive Small Molecules Based on Microbial Chemical Biology and Genetic Analysis

Research Summary

Dong-Chan Oh is interested in discovering novel bioactive small molecules based on microbial chemical biology and genetic analysis.

Small molecules, primarily derived from microbial secondary metabolites, have been playing a key role in drug discovery and development by providing both new chemotypes and new targets. However, over the past two decades, there has been a general decline in the discovery of novel compounds, while drug-resistant diseases have become more widespread. This has made it urgent to discover novel classes of bioactive small molecules with new carbon backbones. Conventional approaches to identify and characterize such compounds have been dominated either by efforts that seek activities inhibiting microbial growth (antibiotics) or simply by the chemical identification of microbial products without any defined knowledge of their biological function.

In recent years, we have begun to understand the genetics and the chemical biology of microbial secondary metabolites. Based on the recent advent of genetic and chemical biological perspectives of natural small molecules, we realized that microbes bear biosynthetic genes and synthesize and secrete pharmaceutically potential small molecules, which affect the physiology of other organisms, such as neighboring microorganisms or symbiotic hosts. My lab is discovering novel small molecules by coupling microbial genetics and chemistry and studying the chemical biology of diverse interspecies interactions among microbes and symbiotic organisms. The significance of our research program lies in the generation of a collection of potential drug lead compounds through characterizing such molecules and studying their biological functions. These could eventually be developed as therapeutic agents or chemical probes, as several other natural products currently in clinical or experimental use demonstrate. My new research strategy will also provide a fundamental understanding of how and why microbes synthesize their secondary metabolites. Currently, my research program is organized using the following directions.

Discovery of New Antibiotic Molecules in Insect–Microorganism Symbiosis
My lab identifies and characterizes antibiotic metabolites from insect–microorganism symbiotic systems, where symbiotic microbes produce bioactive compounds that possibly mediate their symbiotic systems. Recently, we found an interesting insect system that potentially possesses a symbiotic relationship with microorganisms. Dung beetles, important soil recyclers, roll brood balls and lay eggs inside the balls. The beetles' larvae develop inside the balls until they become adults by metamorphism. Dung balls seem to be ideal environments for bacteria and fungi rather than the larvae. However, we observed that the brood balls resist bacterial and fungal infestation under the care and touching of adult female dung beetles through the brooding period. Without this care, the balls degrade, and the survival rate of the larvae decreases dramatically. We assumed that the dung beetles themselves possibly produce antibiotics, but the de novo synthesis of antibacterial peptides does not sufficiently explain the phenomenon that the entire dung ball is resistant to bacterial and fungal infestation, since touching by the female only affects the surface of a brood ball. Therefore, my lab developed a hypothesis that dung beetles have a symbiotic relationship with antibiotic-producing microbes that the dung beetles inoculate when they make the dung balls and touch them. We have investigated one species of dung beetle, Copris tripartitus, and have already isolated more than 100 actinomycete strains from the beetle's larvae and brood balls. Chemical analysis of the microbial strains resulted in the discovery of structurally new phenylpyridine-type compounds and a novel cyclobutane-bearing macrocyclic lactam. My lab will study the symbiotic system of C. tripartitus continuously and discover more antibiotic natural molecules. We will also identify the key antibiotics protecting the larvae and mediating the system. We also plan to study more insect–microorganism symbiotic systems to discover novel antibiotics. In particular, wasps and termites are good candidates for microbial symbiosis.

Fine Genomic and Chemical Analysis of Microorganisms from New Geographic Niches
My lab is focusing on unique microbes from marine environments and selecting chemically unique microbial strains by fine genomic and chemical analysis. Deep-sea microorganisms are potentially prolific and relatively understudied sources for novel bioactive small molecules. For efficient discovery of novel bioactive compounds with distinct carbon skeletons, we need to perform the following three steps: (1) Collecting unique microorganisms from the seafloor or salt pans; (2) analyzing their gene sequences, particularly 16S rDNA for bacteria and 18S rDNA for fungi, which are the index sequences of phylogenetics, to identify taxonomically unique strains; and (3) analyzing their secondary metabolite production and dereplicating known compounds rapidly. My lab has already manufactured samplers that grab sea-bottom sediment and collected 160 microbial strains from the deep-sea sediments collected around Jeju Island in Korea.

Fine genomic analysis is also a key in this aim. Since subtle differences of one nucleotide in the genomes can give rise to totally different chemotypes, fine genomic analysis prior to chemical studies will avoid the study of redundant chemistry and eventually increase efficiency in screening. In addition, my lab utilizes liquid chromatography-mass spectrometry (LC/MS) analysis as a pivotal tool in monitoring the production of secondary metabolites, which requires less than one hour from sample preparation to analysis. LC/MS analysis provides polarity-wise separation of crude microbial culture extracts and valuable information about separated components, such as ultraviolet (UV) and mass spectra. Based on retention times, UV, and MS, my lab can compare observed compounds with a UV database interlinked with the LC/MS operation software, which we have been continuously updating, and a microbial compound database sorted by molecular weights. This will enable the dereplication of known compounds rapidly—within an hour. Through this approach, my lab has recently discovered a novel antifungal macrolide with remarkable inhibition activity against Candida albicans' isocitrate lyase from a marine sediment-derived actinomycete. In addition, we have discovered a novel lasso peptide from Streptomyces sp. isolated from deep-sea sediment. We will continue to seek to discover new and unstudied geographic niches and perform fine genetic and chemical analysis of unique microorganisms for efficient discovery of novel therapeutic agents.

Grants from the Ministries of Education and Technology in South Korea provided partial support for these projects.

As of January 17, 2012