Investigating Microbial Natural Product Biosynthesis

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Microorganisms occupy every habitat on earth and possess an astounding array of metabolic diversity. This metabolic power is used in Nature to drive biogeochemical cycles, and has been harnessed by humans for green chemistry, bioremediation, and the production of chemicals such as antibiotics. Although the crucial role of microbes in the environment and human health is increasingly apparent, characterizing and exploiting their full potential has long been limited by our inability to culture them. Indeed, less than 1% of microorganisms may be grown in laboratory culture, indicating that a vast reservoir of microbial metabolic diversity remains untapped. Isolating total DNA from an environmental sample and expressing these genes in a cultivable bacterial host (metagenomics) can capture this reservoir and provide access to previously unknown microbial enzymes and small molecules with potential to address societal challenges in human health, energy, agriculture, and the environment. Among such challenges, discovering new bioactive organophosphorus compounds is an important goal that can be realized by understanding microbial strategies of phosphonate biosynthesis. The long-term objective of the proposed research program is to discover novel small molecules and biosynthetic enzymes encoded by uncultivated microorganisms. The immediate goals of the proposed research are to discover C-P bond-containing small molecules (phosphonates/phosphinates) and characterize the enzymes involved in their biosynthesis. Phosphonates are small molecule natural products used as herbicides and antibiotics, but relatively few natural phosphonates are known. The proposed research aims to identify novel phosphonates with potential applications in agriculture and medicine, and uncover new enzymes capable of being exploited for biocatalysis and green chemistry applications.