Download or read book The Development of Chemical Tools to Study Cell-cell Communication and Virulence in Gram-positive Bacteria written by Korbin Hong James West and published by . This book was released on 2021 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Over the past 40 years, quorum sensing (QS)-a type of chemical communication used by common bacteria-has been shown to be play an increasingly important role in bacterial communities. QS mediates a wide array of bacterial group behaviors such as initiating infection, mediating symbiosis, and adapting to environmental stimuli. A common QS pathway used by many Gram-positive bacteria is the accessory gene regulator (agr) system, which has been recognized as a key regulator of virulence in several clinically relevant pathogens. Activation of agr QS and its downstream regulation is dependent upon the production and reception of a peptide signal known as the autoinducing peptide (AIP). Interfering with this signaling process using non-native chemical modulators that target the various components of agr represents an approach to attenuate agr QS activity and alter associated bacterial phenotypes. There currently is a dearth of potent and efficacious chemical modulators for the majority of agr systems. Moreover, many of these synthetic ligands have been only examined in vitro, and many questions remain about the modes by which bacteria use agr QS in vivo and the methods by which to best leverage these chemical modulators to reduce bacterial virulence. In this thesis, I describe my work to create, develop, and apply chemical tools to investigate agr QS in three important pathogens. I performed structure-activity relationship (SAR) analyses on the native AIP signal of Listeria monocytogenes and uncovered the most potent agr agonists and antagonists of its agr system to date. These modulators can strongly promote or inhibit biofilm formation, a critical virulence phenotype in L. monocytogenes, demonstrating the utility of chemical control of agr activity. Structural and SAR studies of the AIPs from Staphylococcus epidermidis revealed new structural insights into modulator potency and efficacy, as well as enabling the development of the first agonists capable of activating multiple AgrC receptors. Lastly, I characterized degradable polymeric materials loaded with potent Staphylococcus aureus agr antagonists and demonstrated their ability to attenuate infection in a murine model. The studies presented herein represent significant advances towards developing chemical tools to probe and control agr QS in important Gram-positive bacteria.