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Professor Abigail Doyle Professor Carlson

Most bacteria are surrounded by a cell wall composed of a complex polymeric structure called peptidoglycan that is essential for cell survival. The biosynthetic pathway for production of peptidoglycan and the proteins required for its assembly have been the targets for many antibacterial agents. For example, penicillin-binding proteins (PBPs), which polymerize and crosslink strands of peptidoglycan also have affinity for the beta-lactam antibiotic penicillin. PBPs are classified into three groups based upon their molecular weight, conserved amino acid motifs and function. These proteins all contain a serine in their peptidase domain that is required for catalysis. Penicillin hinders PBP function by forming a stable acyl-enzyme intermediate with this residue, which in turn inhibits crosslinking of peptidoglycan.

Despite the effectiveness of beta-lactam antibiotics, bacterial resistance has arisen very rapidly. A more detailed understanding of the mechanism of peptidoglycan synthesis may be the key for design of new and more effective antibiotics. We have developed fluorescently-labeled small molecule probes to visualize the activity of PBPs directly in live cells. Small molecule-conjugated fluorophores can provide superior temporal resolution than more traditional strategies, such as protein fusion, and their activity can be modulated by dose. These compounds are also generally easy to use and enable visualization in a broad range of organisms to explore the construction and remodeling of peptidoglycan.

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Kocaoglu O, Calvo RA, Sham LT, Cozy LM, Lanning BR, Francis S, Winkler ME, Kearns DB, Carlson EE.
ACS Chem Biol. 2012 Oct 19;7(10):1746-53. doi: 10.1021/cb300329r. Epub 2012 Aug 21.
The peptidoglycan cell wall is a common target for antibiotic therapy, but its structure and assembly are only partially understood. Peptidoglycan synthesis requires a suite of penicillin-binding proteins (PBPs), the individual roles of which are difficult to determine because each enzyme is often dispensable for growth perhaps due to functional redundancy...Read More
Sharifzadeh S, Boersma MJ, Kocaoglu O, Shokri A, Brown CL, Shirley JD, Winkler ME, Carlson EE.
ACS Chem Biol. 2017 Nov 17;12(11):2849-2857. doi: 10.1021/acschembio.7b00614. Epub 2017 Oct 18.
Peptidoglycan (PG) is a mesh-like heteropolymer made up of glycan chains cross-linked by short peptides and is the major scaffold of eubacterial cell walls, determining cell shape, size, and chaining. This structure, which is required for growth and survival, is located outside of the cytoplasmic membrane of bacterial cells, making it highly accessible to antibiotics...Read More
Watt VM, Yip CC
Biochem Biophys Res Commun. 1989 Oct 31;164(2):671-7.
Receptors for atrial natriuretic peptide (ANP) are heterogeneous: an approximately 140-kDa receptor exhibits ANP-stimulated guanylate cyclase activity whereas an approximately 65-kDa receptor is thought to act only as a clearance-storage protein...Read More