Princeton University Library Catalog

Synthesis and Assay of a Clickable Inhibitory Peptide for the agr Quorum Sensing System in Staphylococcus aureus

Wang, Ashley Chao-Min [Browse]
Senior thesis
Muir, Tom [Browse]
Princeton University. Department of Chemistry [Browse]
Class year:
83 pages
Summary note:
The regulation of virulence in human pathogen Staphylococcus aureus is achieved by the accessory gene regulator (agr) operon, in which the interaction between extracellular autoinducing peptide (AIP) signaling molecule and the agr cognate (AgrC) membrane receptor plays a critical role. Recently, the Muir lab discovered the truncated AIP-II (trAIP-II) as a global inhibitor against different agr specificity groups, which opens up potential applications in biomedical research. However, the possibility of incorporating this molecule onto readily available surface materials has not yet been explored. The goal of this research project is to investigate the use of surfaces coated with inhibitors as a strategy to inhibit virulence induction in S. aureus. To model this idea, we first synthesized a derivatized “clickable” trAIP-II containing an alkyne handle at the Nterminus, which acts as a global inhibitor to block the quorum-sensing communication system in S. aureus. Then, we incorporated the molecule onto a polymer via Cu(I)- catalyzed alkyne-azide cycloaddition (CuAAC); this polymer models the linkers used in surface material modification. In this study, we not only successfully synthesized both the alkynated trAIP-II inhibitor and an alkynated AIP-I control, but also conjugated the alkynated species onto PEG-polymers. Using the β-lactamase/nitrocefin bioassays, we demonstrated that the inhibitors and control activators all function as expected: the former inhibits S. aureus activity while the latter promotes activation. In conclusion, our study shows promising results and offers great potential for future research in device-related applications and antimicrobial combination therapies.