- Harvard Medical School, Department of Microbiology
- Harvard University, Department of Chemistry and Chemical Biology
- Biological and Biomedical Sciences PhD Program
- Chemical Biology PhD Program
Research in the Walker laboratory falls into two major areas. One is primarily directed towards addressing the problem of antibiotic resistance. We investigate bacterial pathways that may be targets for new antibiotics. We carry out detailed mechanistic and structural studies of known antibiotic targets with the expectation that a better understanding of how they function will lead to the ability to design improved antibiotics. We study the mechanisms of action of natural product antibiotics in order to understand the strategies nature has employed to kill bacteria. We work on strategies to discover new antibiotics as well as methods to modify natural product antibiotics to improve their properties. Finally, we explore the mechanisms by which resistance can develop to selected antibiotics. In our studies we employ biophysical approaches to study protein structure, biochemistry to probe enzyme function, genetics to explore gene function in selected microorganisms and to manipulate natural product biosynthetic pathways, and high throughput screening to discover compounds that interfere with biosynthetic pathways or processes of interest. We also make use of synthetic organic chemistry to enable some of our projects. Microorganisms we manipulate in the laboratory include Escherichia coli, Enterococcus faecalis, and Staphylococcus aureus.
The second major research area focuses on understanding human O-GlcNAc transferase (OGT), a glycosyltransferase that modulates signaling pathways linked to glucose metabolism. We are interested in the structure and function, and in developing strategies to probe its biological roles.
Janetzko J, Walker S. Aspartate Glycosylation Triggers Isomerization to Isoaspartate. J Am Chem Soc. 2017 Mar 08; 139(9):3332-3335. PMID: 28207246. View in: PubMed
Schaefer K, Matano LM, Qiao Y, Kahne D, Walker S. In vitro reconstitution demonstrates the cell wall ligase activity of LCP proteins. Nat Chem Biol. 2017 Apr; 13(4):396-401. PMID: 28166208. View in: PubMed
Janetzko J, Trauger SA, Lazarus MB, Walker S. How the glycosyltransferase OGT catalyzes amide bond cleavage. Nat Chem Biol. 2016 Nov; 12(11):899-901. PMID: 27618188. View in: PubMed
Levine ZG, Walker S. The Biochemistry of O-GlcNAc Transferase: Which Functions Make It Essential in Mammalian Cells? Annu Rev Biochem. 2016 Jun 02; 85:631-57. PMID: 27294441. View in: PubMed
Lee W, Schaefer K, Qiao Y, Srisuknimit V, Steinmetz H, Müller R, Kahne D, Walker S. The Mechanism of Action of Lysobactin. J Am Chem Soc. 2016 Jan 13; 138(1):100-3. PMID: 26683668. View in: PubMed