Gram Positive Quorum Sensing
Several Gram-positive pathogens that pose a major threat to human health, including Staphylococcus aureus, Staphylococcus epidermidis, and Listeria monocytogenes, use an accessory gene regulator (agr) quorum sensing system to regulate virulence. Gram-positive quorum sensing in these bacteria is driven by diverse small autoinducing peptides (AIPs). The Blackwell lab has developed some of the most potent peptides, peptidomimetics, and small molecules to modulate these quorum sensing systems. We use these chemical tools to probe the mechanistic details of the agr system and to further study the infection phenotypes associated with modulating Gram-positive quorum sensing.
Featured Projects
Novel quorum sensing modulators
Several projects aim to understand key structural features of quorum sensing modulators across agr systems. With information gleaned from detailed structure-activity relationship studies, we rationally design and synthesize analogs of native AIPs, chimeric AIPs, and peptidomimetics, and test these compounds in cell-based reporter assays. Many of these compounds have strong antagonistic or agonistic activities; we seek to understand the molecular features of these compounds that engender such activity profiles.
We have also identified novel small molecule inhibitors of the S. aureus agr quorum sensing system in a high throughput screen of a commercial small molecule library. We are developing synthetic routes to these compounds to both discover agr inhibitors with increased potency and stability. We are also designing reactive probes to gather insights into their mechanisms of action.
We are developing in vitro assays to gain a deeper mechanistic understanding of the activity of our quorum sensing modulators on the agr system. We are also interested in developing cell-based systems to biosynthesize analogs of native AIPs, which will allow us to learn more about the flexibility of the agr system in processing non-native AIPs and efficiently produce a wide range of additional AIP analogues to test for activity. These engineered organisms will also facilitate competition studies with other bacteria and in in vivo infection models.
Read more:
Agr-related phenotypic characterization
With the suite of agr modulators developed by our lab, we have explored the effects of quorum sensing modulation on numerous phenotypes, including blood hemolysis, toxic shock syndrome toxin production, chitinase activity, biofilm formation, and virulence in mouse models of infection. Through this suite of phenotypic assays, we can gain a more holistic picture of the modes by which quorum sensing modulation can affect the infectivity of these pathogens. We are interested in exploring how agr modulators may impact phenotypes in complex, multi-species systems as well.
Read more:
