Jason M. Crawford
Small molecule signaling in host-bacteria interactions
The Crawford laboratory focuses on developing and systematically applying genome sequence-guided methods for the discovery of novel genetically encoded small molecules from mutualistic and pathogenic bacteria. To decode the chemical-signaling events between microbes and their animal hosts, our research combines the disciplines of natural product biosynthesis, microbial small molecule characterization, molecular mode of action, and microbiology.
With the explosion of microbial genome sequence data available over the last five years, it is now evident that microbes harbor the genetic potential to contribute several orders of magnitude more pharmacologically-relevant molecules than are currently known. However, tight regulatory control of the majority of bioactive small molecule metabolic pathways in the producing organism blocks their functional elucidation in the lab. To overcome this challenge, we recapitulate natural host-pathogen interactions to understand and stimulate unknown biosynthetic pathways that may not normally be turned on under typical lab conditions. In addition, we utilize microbial genomic analyses, protein biochemistry, and genetic manipulation to discover the novel enzyme systems and their functional roles in the context of their ecological niche. Many of the highly unusual "orphan" biosynthetic gene clusters identified in our analysis are suspected of synthesizing novel, structurally diverse, and biologically active small molecules. These types of "cryptic" naturally produced molecules often regulate complex interactions with their animal hosts, hold a rich history of being utilized as human drugs, and serve as excellent molecular probes for identifying new drug targets for a wide variety of diseases.
Our group is particularly interested in the molecular communications between a family of prolific bioactive small molecule-producing Gammaproteobacterial pathogens and their afflicted animal hosts – insects and humans. The underlying theme that bridges the two host systems is that the bacteria must productively or combatively modulate the host organisms’ innate immune systems. Our functional genomic approach aims to uncover new bacterial biosynthetic systems evolutionarily selected to chemically modulate host immunobiology and exploit them for biomedical applications.