Alexander R. Horswill, Ph.D.
Ph.D., University of Wisconsin, 2001 |
Assistant Professor of Microbiology Campus address: 540F EMRB Mailing address: 431 Newton Rd. 540F Eckstein Medical Research Building Iowa City, IA 52242 Phone: 319-335-7783 Email: |
Bacterial cell-to-cell communication using autoinducing peptides
Many critical processes in bacteria are regulated by cell density. By producing chemical signals, bacteria can communicate and coordinate regulatory events in large populations. These signals accumulate to a critical threshold and elicit a regulatory response at the appropriate cell density. This phenomenon of density-dependent regulation is frequently termed quorum sensing or autoinduction, and the signals controlling this process are acyl-homoserine lactones (HSLs) in Gram negative bacteria and peptides in Gram positive bacteria. While HSLs have been investigated extensively, studies on peptide regulation have lagged behind, even though many Gram positive bacteria regulate pathogenesis using these signals.
My research focuses on the peptide quorum sensing system of Staphylococcus aureus. The agr locus of this bacterium produces an extracellular peptide signal, called an autoinducing peptide (AIP). At the correct cell population, this signal controls expression of the virulence response, including down-regulating the expression of surface proteins, such as adhesins and antigens, and up-regulating the expression of virulence factors, such as hemolysins, proteases, and toxins. Structural studies have determined that the S. aureus AIP is an eight-residue peptide, with the five C-terminal residues cyclized into a thiolactone ring. However, there is little information available about the proteins involved in the maturation and export process, and the details of the biosynthetic mechanism remain unclear. My laboratory will take genetic, molecular, and biochemical approaches towards defining the route of AIP biosynthesis and the mode of action of these signals. With a better understanding of the AIP system, it will be possible to develop AIP inhibitors that could block S. aureus virulence. We will explore cutting-edge peptide technologies to discover such inhibitors and investigate their implementation in S. aureus.
Recent efforts have suggested that S. aureus quorum sensing and biofilm formation are interconnected. The ability of S. aureus to develop biofilms on medical implants is an important determinant in infections, high-lighting the need for more studies in this area. As we learn more about AIP biosynthesis and regulation, this research will be extended toward studies on biofilms, with a goal of improving our understanding of this connection.
Recent publications
Thoendel, M., and A.R. Horswill. 2009. Identification of Staphylococcus aureus AgrD residues required for autoinducing peptide biosynthesis. J Biol Chem June 11 [Epub ahead of print].
Malone, C.L., B.R. Boles, K.J. Lauderdale, M. Thoendel, J.S. Kavanaugh, and A.R. Horswill. 2009. Fluorescent reporters for Staphylococcus aureus. J Microbiol Methods 77:251-260.
Lauderdale, K.J., B.R. Boles, A.L. Cheung, and A.R. Horswill. 2009. Interconnections between Sigma B, agr, and proteolytic activity in Staphylococcus aureus biofilm maturation. Infect Immun 77:1623-1635.