Our longterm goal is to understand how the bacterial cell envelope is assembled, how its assembly is coordinated with cell division, and how we can exploit our knowledge to develop strategies to overcome antibiotic-resistant infections. Our primary model system is Staphylococcus aureus. We have developed a wide range of tools and methods to study peptidoglycan biosynthesis and degradation. We have reconstituted lipo- and wall teichoic acid biosynthesis pathways. We have developed new approaches to discover inhibitors of biosynthetic enzymes in these pathways, and we have established genome-wide approaches that use small molecules to uncover connections between pathways. We now want to combine our tools and approaches with other technologies to develop an integrated picture of how extracellular and intracellular biosynthesis pathways are coordinated through the cell membrane to allow the cell to grow and divide.
To read more about some of our work on the bacterial cell envelope, please see the selected publications below.
SELECTED PUBLICATIONS
Hesser, A. R.; Schaefer, K.; Lee, W.; Walker, S. Lipoteichoic acid polymer length is determined by competition between free starter units. Proc. Natl. Acad. Sci. U. S. A. 2020, 117 (47), 29669-29676. [PubMed Link] [Publisher Link]
#Schaefer, K.; #Owens, T. W.; Page, J. E.; Santiago, M.; Kahne, D.; Walker, S. Structure and reconstitution of a hydrolase complex that may release peptidoglycan from the membrane after polymerization. Nat. Microbiol. 2020, 6, 34-43. [PubMed Link] [Publisher Link]
Do, T.; Schaefer, K.; Santiago, A. G.; Coe, K. A.; Fernandes, P. B.; Kahne, D.; Pinho, M. G.; Walker, S. Staphylococcus aureus cell growth and division are regulated by an amidase that trims peptides from uncrosslinked peptidoglycan. Nat. Microbiol. 2020, 5 (2), 291-303. [PubMed Link] [Publisher Link]
Taguchi, A.; Welsh, M. A.; Marmont, L. S.; Lee, W.; Sjodt, M.; Kruse, A. C.; Kahne, D.; Bernhardt, T. G.; Walker, S. FtsW is a peptidoglycan polymerase that is functional only in complex with its cognate penicillin-binding protein. Nat. Microbiol. 2019, 4, 587-594. [PubMed Link] [Publisher Link]
Santiago, M.; Lee, W.; Fayad, A. A.; Coe, K. A.; Rajagopal, M.; Do, T.; Hennessen, F.; Srisuknimit, V.; Müller, R.; Meredith, T. C.; Walker, S. Genome-wide mutant profiling predicts the mechanism of a Lipid II binding antibiotic. Nat. Chem. Biol. 2018, 14 (6), 601-608. [PubMed Link] [Publisher Link]
Schaefer, K.; Owens, T. W.; Kahne, D.; Walker, S. Substrate Preferences Establish the Order of Cell Wall Assembly in Staphylococcus aureus. J. Am. Chem. Soc. 2018, 140 (7), 2442-2445. [PubMed Link] [Publisher Link]
Schaefer, K.; Matano, L. M.; Qiao, Y.; Kahne, D.; Walker, S. In vitro reconstitution demonstrates the cell wall ligase activity of LCP proteins. Nat. Chem. Biol. 2017, 13 (4), 396-401. [PubMed Link] [Publisher Link]
Pasquina, L.; Santa Maria, J. P.; Wood, B. M.; Moussa, S. H.; Matano, L. M.; Santiago, M.; Martin, S. E. S.; Lee, W.; Meredith, T. C.; Walker, S. A synthetic lethal approach for compound and target identification in Staphylococcus aureus. Nat. Chem. Biol. 2016, 12 (1), 40-45. [PubMed Link] [Publisher Link]
Qiao, Y.; Lebar, M. D.; Schirner, K.; Schaefer, K.; Tsukamoto, H.; Kahne, D.; Walker, S. Detection of Lipid-Linked Peptidoglycan Precursors by Exploiting an Unexpected Transpeptidase Reaction. J. Am. Chem. Soc. 2014, 136 (42), 14678-14681. [PubMed Link] [Publisher Link]
Santa Maria, J. P.; Sadaka, A.; Moussa, S. H.; Brown, S.; Zhang, Y. J.; Rubin, E. J.; Gilmore, M. S.; Walker, S. Compound-gene interaction mapping reveals distinct roles for Staphylococcus aureus teichoic acids. Proc. Natl. Acad. Sci. U. S. A. 2014, 111 (34), 12510-12515. [PubMed Link] [Publisher Link]
Brown, S.; Xia, G.; Luhachack, L. G.; Campbell, J.; Meredith, T. C.; Chen, C.; Winstel, V.; Gekeler, C.; Irazoqui, J. E.; Peschel, A.; Walker, S. Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids. Proc. Natl. Acad. Sci. U. S. A. 2012, 109 (46), 18909-18914. [PubMed Link] [Publisher Link]
Campbell, J.; Singh, A. K.; Santa Maria, J. P.; Kim, Y.; Brown, S.; Swoboda, J. G.; Mylonakis, E.; Wilkinson, B. J.; Walker, S. Synthetic Lethal Compound Combinations Reveal a Fundamental Connection between Wall Teichoic Acid and Peptidoglycan Biosynthesis in Staphylococcus aureus. ACS Chem. Biol. 2011, 6 (1), 106-116. [PubMed Link] [Publisher Link]
Banner image: fluorescence microscopy image of Staphylococcus aureus cells stained with the membrane dye Nile Red, courtesy of Dr. Truc Do