Integrated Calendar

Staphylococcus aureus is a dangerous human pathogen that utilizes cyclic autoinducing peptides (AIPs) to synchronize group-beneficial phenotypes in a process termed quorum sensing (QS). This deadly pathogen uses an impressive arsenal of virulence factors, all under the control of the accessory gene regulator (agr) QS circuit. To date, four AIP:AgrC pairs have been identified in S. aureus, allowing this pathogen to be organized into four specificity groups. The broad aim of my postdoctoral research is to characterize the agr QS system using chemical based tools and to develop strategies for clearing S. aureus infections using novel QS inhibitors and materials. I initiated my research working on the group-III S. aureus, the causative agent of most toxic shock syndrome cases in humans and emerging as a prevalent contributor to other human infections. To this end, I developed an optimized synthetic route for the preparation of the native AIPs and their analogs. Using these protocols, I was able to conduct an extensive structure-activity relationship study of AIP-III and find potent agr inhibitors that are active in the picomolar range. Notably, these compounds attenuate virulence factor production in wild-type S. aureus at picomolar concentrations; a significant discovery, as compounds that block QS in wild-type bacteria are rare. I addition, structural analysis of representative analogs provided the first molecular-level view of any AIP or analog thereof and suggested a mechanism for AgrC-III receptor modulation. This study could provide new pathway to the development of anti-virulence approaches in S. aureus.

Phase field crystal (PFC) models describe dynamics in liquid-solid systems over diffusive time scales and atomistic length scales. These basic features suggest a potential suitability for examining glass formation over time-temperature ranges inaccessible to conventional atomistic approaches. In this talk, the formulation and study of PFC models for simple colloidal and atomic/molecular glass forming systems will be discussed. It will be shown that models with a few minimal features can produce dynamics consistent with a fragile glass transition and the central predictions of mode-coupling theory. An observed correlation between fragility and a large dynamic-elastic length scale will be discussed. Finally, the issue of access to long times is highlighted by a physically motivated time scaling that results in qualitative agreement with basic glass transition phenomenology across 12 orders of magnitude in time.