Harvard Medical School
 
Suzanne Walker  

Dept. of Microbiology and Immunobiology

Harvard Medical School

HIM, Room 1013

4 Blackfan Circle

Boston, MA 02115

phone: 617-432-5488

fax: 617-738-7664

     

Research Summary

Antibiotic resistance has become a major problem worldwide and new compounds and approaches to overcome resistant microorganisms are desperately needed.  A major focus of our laboratory is to elucidate metabolic pathways that are known or potential antibiotic targets, and then to explore strategies to inhibit them. Pathways of special interest include peptidoglycan biosynthesis and wall teichoic acid biosynthesis. We also have a longstanding interest in the structure, function, and inhibition of glycosyltransferases, including eukaryotic glycosyltransferases, and are currently working on the chemistry and biology of human O-GlcNAc transferase.

We take a multidisciplinary approach in our investigations, employing chemical synthesis, enzymology, bacterial genetics, cell biology, high-resolution microscopy, structural biology, and high throughput screening.  Our laboratory pioneered the use of chemically synthesized substrates to study the membrane-linked steps of peptidoglycan biosynthesis and we have used these substrates to make fundamental contributions to understanding peptidoglycan biosynthetic enzymes and the antibiotics that inhibit them.  Our studies on bacterial peptidoglycan have expanded into successful collaborative program with the Kahne Lab in the Chemistry Department of Harvard University.  

We recently extended our approaches to studying membrane-associated biosynthetic pathways to wall teichoic acids, a major polymer found on the surface of Gram-positive organisms.  We established the pathways for wall teichoic acid biosynthesis in Staphylococcus aureus and Bacillus subtilis W23.  We discovered the first small molecule antibiotics that target WTA biosynthesis, and we have shown using synthetic lethal compound combinations that WTAs play a critical role in the assembly of the septal peptidoglycan biosynthetic machinery.   We think WTAs function as scaffolds that recruit other proteins to the division site.  We are currently working  to elucidate the molecular mechanisms that couple the WTA and PG biosynthetic pathways to ensure proper cell division.


Selected Publications

Lazarus MB, Nam Y, Jiang J, Sliz P, Walker S. Structure of human O-GlcNAc transferase and its complex with a peptide substrate. Nature 2011; 469: 564-7.

Wang TS, Lupoli TJ, Sumida Y, Tsukamoto H, Wu Y, Rebets Y, Kahne DE, Walker S. Primer Preactivation of Peptidoglycan Polymerases. J. Am. Chem. Soc. 2011; 133:8528-30.

Campbell J, Singh AK, Santa Maria J, Kim Y, Brown S, Swoboda J, Mylonakis E, Wilkinson B, Walker S. Synthetic lethal compound combinations reveal a fundamental connection between wall teichoic acid and peptidoglycan biosynthesis in Staphylococcus aureus. ACS Chem. Biol. 2011; 6:106-16.

Perlstein DL, Wang TS, Doud EH, Kahne D, Walker S. The role of the substrate lipid in processive glycan polymerization by the peptidoglycan glycosyltransferases. J. Am. Chem. Soc. 2010; 132:48-9.

Brown S, Meredith T, Swoboda S, Walker S. Staphylococcus aureusand Bacillus subtilis 23 make polyribitol wall teichoic acids by different enzymatic pathways, Chemistry and Biology 2010; 17:1101-10.

Swoboda JG, Meredith TC, Campbell J, Brown S, Suzuki T, Bollenbach T, Malhowski AJ, Kishony R, Gilmore MS, Walker S. Discovery of a small molecule that blocks wall teichoic acid biosynthesis in Staphylococcus aureus. ACS Chem. Biol. 2009; 4:875-83.

Brown S, Zhang YH, Walker S.  A Revised Pathway Proposed for Staphylococcus aureus Wall Teichoic Acid Biosynthesis Based on In Vitro Reconstitution of the Intracellular Steps.  Chemistry and Biology 2008; 15:12-21.

Ostash B, Doud EH, Lin C, Ostash I, Perlstein DL, Fuse S, Wolpert M, Kahne D, Walker S. Complete characterization of the seventeen step moenomycin biosynthetic pathway. Biochemistry 2009; 48:8830-41.

Yuan Y, Fuse S, Ostash B, Sliz P, Kahne D, Walker S.  Structural analysis of the contacts anchoring moenomycin to peptidoglycan glycosyltransferases and implications for antibiotic design.  ACS Chem. Biol. 2008;3:429-36.

Perlstein DL, Zhang Y, Wang TS, Kahne DE, Walker S.  The direction of glycan chain elongation by peptidoglycan glycosyltransferases.  J. Am. Chem. Soc. 2007; 129:12674-12675.

Yuan Y, Barrett D, Zhang Y, Kahne D, Sliz P, and Walker S, Crystal structure of a peptidoglycan glycosyltransferase suggests a model for processive glycan chain synthesis, Proc. Natl. Acad. Sci. USA 2007; 104:5348-5353.

Tiyanont K, Doan T, Lazarus MB, Fang X, Rudner DZ, and Walker S, Imaging Peptidoglycan Biosynthesis in Baccillus subtilis with Fluorescent Antibiotics, Proc. Natl. Acad. Sci. USA, 2006;103:11033-11038.

Hu Y, Chen L, Ha S, Gross B, Falcone B, Walker D, Mokhtarzadeh M, Walker S. Crystal Structure of MurG: UDP-GlcNAc Complex Reveals Common Structural Principles of a Superfamily of Glycosyltransferases. Proc. Natl. Acad. Sci. USA 2003; 100:845-849.

Lo M, Helm J, Sarngadharan G, Pelczer I, Walker S. A New Structure for the Substrate-Binding Antibiotic Ramoplanin. J. Am. Chem. Soc. 2001; 123:8640-8641.

Lo M, Men H, Branstrom A, Helm J, Yao N, Goldman R, Walker S. A New Mechanism of Action Proposed for Ramoplanin. J. Am. Chem. Soc. 2000;122:3540-1.

Ha S, Chang E, Lo M, Men H, Park P, Ge M, Walker S. The Kinetic Characterization of Escherichia coli MurG Using Synthetic Substrate Analogues.  J. Am. Chem. Soc. 1999; 121:8415-8426.

Men H, Park P, Ge M, Walker S.  Substrate Synthesis and Activity Assay for MurG. J. Am. Chem. Soc. 1998; 120:2484-2485.