Utilizing chemical synthesis and chemical biology approaches to study bacterial quorum sensing - quorum sensing (QS) is a cell-cell communication mechanism utilized by bacteria to regulate many…

The National Institute of General Medical Sciences awarded the Board of Regents of Nevada System of Higher Education (operating as University of Nevada, Reno) $447,736 on July 15, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to support research utilizing chemical synthesis and chemical biology approaches to study bacterial quorum sensing.

The award funds investigation of quorum sensing as a cell-cell communication mechanism in bacteria, with focus on deciphering molecular interactions governing signal-receptor binding in gram-positive bacterial species. Specifically, the research examines autoinducing peptide pathways—both RRNPP-type self-signaling circuitries and two-component signal transduction systems—to define key peptide-protein interactions that drive receptor activation and specificity. The work aims to provide insight into receptor function at the molecular level and identify potential novel avenues to attenuate bacterial infections through modulation of quorum sensing circuits.

Performance of the award occurs in Reno, Nevada, with a period of performance running through March 31, 2031. This is a Project Grant, the standard assistance type for investigator-initiated biomedical research under NIGMS.

Utilizing chemical synthesis and chemical biology approaches to study bacterial quorum sensing - quorum sensing (QS) is a cell-cell communication mechanism utilized by bacteria to regulate many symbiotic and pathogenic phenotypes. As such, QS has attracted considerable attention as a means to control bacterial behaviors. Although diverse, QS circuits generally rely on the production, secretion, and detection of a chemical signal, or pheromone. The concentration of the signal is directly proportionate to the bacterial population, and at high concentration, binds and activates a cognate receptor, leading to altered expression of genes involved in group behaviors. From a chemical perspective, deciphering the molecular interactions that govern signal:receptor binding and lead to receptor activation would provide a potential novel avenue to attenuate bacterial infections. Gram-positive bacterial species generally utilize QS circuitries that are centered on peptidic signals termed autoinducing peptides (aips). These peptide-based circuitries fall under one of two categories: the self- signaling pathways, also referred to as the rrnpp-type QS circuitries, and the two-component signal transduction systems (tcstss). In both circuitry types the AIP precursor is being processed and secreted outside of the cell, with the main difference being that in the self-signaling pathways the mature AIP is being imported back to the cell to bind and activate a cytosolic receptor, whereas in the tcsts circuitries the mature AIP binds and activates a transmembrane receptor. Defining the key peptide:protein interactions that drive AIP:receptor binding and lead to QS activation will provide important insight regarding the receptor function at the molecular level, including the key residues and conformational changes that lead to receptor specificity and drive receptor activation. The long-term goal of the TAL-GAN lab is to utilize bacterial QS pathways to study complex bacterial communities in their natural niches. To this end, in the past decade, through comprehensive systematic analyses of the AIP:receptor interactions that govern tcsts-type and rrnpp-type circuitries of different gram-positive bacteria, we exhibited that small structural changes to the AIP sequences could lead to significant alterations in AIP function; developed synthetic peptidomimetic aips with improved activities and pharmacological properties; and revealed the first known crosstalk between tcsts-type QS circuitries of two related species where an AIP signal of one species can effectively activate QS in the other species. In the next five years, we plan to continue challenging the status-QUE by utilizing chemical synthesis, chemical biology, and structural biology approaches to characterize the molecular interactions that govern AIP:receptor binding and determine the key residues and structural features of both AIP and receptor that regulate QS modulation. This knowledge will allow US to delineate detailed mechanisms of receptor function at the molecular level, and design novel AIP-based synthetic QS modulators.