Gray Lab

Research Overview

Our research interests over the past decade have centered on Gram positive bacterial pathogenesis. The majority of these studies have been performed with the bacterial pathogen Staphylococcus aureus, which is one of the most frequent causes of bacterial infections in healthcare and community settings. Antibiotic resistance in this pathogen, such as methicillin-resistant S. aureus (MRSA), has continued to rise and become epidemic in many healthcare settings, limiting available treatment options and leading to worse patient outcomes.

Within the area of S. aureus research, our group has focused on variety of topics that includes quorum sensing signal production, biofilm development mechanisms, virulence factor function in host pathogen interactions, and therapeutic development. For some of these areas, we’ve taken a collaborative approach to advancing the science and this strategy has been successful through both publications and obtaining funding. 

Biosynthesis of Gram positive cyclic peptide quorum-sensing signals

virulence pathwayOur early publications focused on S. aureus peptide quorum-sensing signals (autoinducing peptides or AIPs). We investigated molecular and biochemical mechanisms for biosynthesis and developed alternative strategies for their biosynthesis. More specifically, we:

  • Discovered that the Type I signal peptidase SpsB is important for AIP biosynthesis
  • Identified new residues in the AgrB endopeptidase and AgrD peptide that are essential for building the AIP signals
  • Reassessed AgrB membrane topology using the scanning cysteine accessibility method

We continue to investigate the function of AgrB and mechanism of AgrB inhibitors

Quorum-sensing and biofilm interactions

biofilm formationMy group’s interest in S. aureus quorum-sensing lead us into biofilm studies on this important pathogen. We determined that the quorum-sensing system activates a biofilm dispersal pathway, and follow-up studies identified the cysteine proteases (Staphopains) as being the important end products of this pathway. Currently, we are investigating the targets of Staphopains in the S. aureus biofilm matrix.

Biofilm development mechanisms

Staph BiofilmOur interest in the S. aureus biofilm dispersal pathway broadened our interest in bacterial biofilm biology. In collaboration with the Center for Staphylococcal Research at UNMC, we have been and continue to investigate a number of properties of Staphylococcal biofilms. My group’s part of this collaborative effort lead to the discovery that the secreted nuclease (Nuc) has a major impact on the biofilm matrix, and we demonstrated that Nuc is a virulence factor regulated by the Sae two-component system. In collaboration with Dr. James McNamara (Iowa), we demonstrated that Nuc can be used as an imaging tool to detect S. aureus infection. Recently, we developed a new approach to identify extracellular DNA (eDNA) binding proteins, and currently we are characterizing proteins discovered from this screen.

Host-pathogen interactions

We have been investigating S. aureus host-pathogen interactions in collaboration with other laboratories. Most prominently with Dr. William Nauseef (Iowa) and in the context of S. aureus interactions with human neutrophils.  Our primary interest is understanding the roles of S. aureus secreted enzymes.  We have investigated the function of extracellular proteases, nucleases, hyaluronidases, and phospholipases during infection.

Targeting quorum sensing for anti-virulence therapy

Our interest in bacterial quorum sensing lead to efforts to target this regulatory pathway for development of anti-virulence therapies. Through collaborative efforts with several laboratories, we helped identify a couple new compounds that inhibit S. aureus quorum sensing and infection development by targeting the AgrA DNA binding protein. We currently are investigating the mechanisms of new leads.

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Location
Eckstein Medical Research Building
Room 540F
431 Newton Rd
Iowa City, IA 52242

Contact Info
Phone: (319) 335-7996
Email: alex-horswill@uiowa.edu