Natural products biosynthesis, bacterial signalling, X-ray crystallography
Research in the Nair lab focuses on understanding the basis for regulation of bacteria by small molecule natural products. Our laboratory uses classical biochemical and microbiological techniques, in combination with biophysical methods (in particular X-ray crystallography) to decipher how microbes utilize small molecules to establish ecological niches, and combat against the colonization of antagonistic species that may compete for limited resources. This research focus is predicated upon the notion that knowledge of such interactions drives the discovery and development of natural products that can be used to combat the growth of pathogenic bacteria.
Ribosomally synthesized peptide antibiotics: A main research focus in our laboratory is on biosynthetic enzymes that modify ribosomally encoded peptides to yield macrocyclic natural products. We are specifically focused on understanding the mechanism for the synthesis of two classes of such compounds: lantibiotics and cyanobactins. For both classes of natural products, the genetic nature of the precursor and the modular architecture of the modification/processing enzymes may be exploited to yield novel molecules with improved therapeutic applications. Our work on lantibiotics, in collaboration with the van der Donk laboratory (Chemistry: UIUC), has been aimed at characterization of several enzymes involved in biosynthesis. Our work on cyanobactin, in collaboration with Eric Schmidt (Medicinal Chemistry: Utah) focuses on structure-function characterization of enzymatic pathways for the production of these heterocyclized macrocyclic marine natural products.
Phosphonate biosynthesis and engineering: We are members of the Mining Microbial Genomes theme within the Institute of Genomic Biology (van Der Donk: Chemistry, Metcalf: Microbiology and Zhao: Chemical Engineering). In collaboration with the members of this theme, we are focused on characterization of enzymes involved in the biosynthesis of phosphonate antibiotics, with the aim of using the structural data to reprogram these enzymes to produce novel compounds.
Bacterial inter- and intracellular communication: Bacteria can utilize small molecules as signals and we are focusing on elucidating the mechanisms underlying this process. In quorum sensing, bacteria coordinate population growth by utilizing small molecule inducers (typically acylhomoserine lactones). When the population density exceeds some threshold, these autoinducers bind to their cognate receptor and activate the transcription of various genes. A second class of inter-cellular communication is predicated upon the action of a diffusible signal factors that are chemically distinct from quorum sensing autoinducers. These classes of compounds activate the production or degradation of a second messenger, cyclic diguanylate (or cyclic di-GMP) that act as downstream effectors for various signaling pathways. In theory, as each of these pathways are regulated by small molecules, they represent ideal targets for therapeutic intervention against bacterial growth.