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  • lactones identified as a privileged scaffold for the generation of PBP-selective probes and these compounds were used for imaging of the essential proteins, PBP2x and PBP2b, in Streptococcus pneumoniae
    10/20/17

    Researchers identify compounds for imaging proteins in pneumonia

Researchers working with Professor Erin Carlson have identified β-lactones as a privileged scaffold for the generation of penicillin-binding proten (PBP)-selective probes and utilized these compounds for imaging of the essential proteins, PBP2x and PBP2b, in Streptococcus pneumoniae. This research, "Novel Electrophilic Scaffold for Imaging of Essential Penicillin-Binding Proteins in Streptococcus pneumoniae," was recently published in ACS Chemical Biology (DOI: 10.1021/acschembio.7b00614).

According to the abstract: "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. Penicillin-binding proteins (PBPs) are essential for construction of PG and perform transglycosylase activities to generate the glycan strands and transpeptidation to cross-link the appended peptides. The β-lactam antibiotics, which are among the most clinically effective antibiotics for the treatment of bacterial infections, inhibit PBP transpeptidation, ultimately leading to cell lysis. Despite this importance, the discrete functions of individual PBP homologues have been difficult to determine. These major gaps in understanding of PBP activation and macromolecular interactions largely result from a lack of tools to assess the functional state of specific PBPs in bacterial cells. We have identified β-lactones as a privileged scaffold for the generation of PBP-selective probes and utilized these compounds for imaging of the essential proteins, PBP2x and PBP2b, in Streptococcus pneumoniae. We demonstrated that while PBP2b activity is restricted to a ring surrounding the division sites, PBP2x activity is present both at the septal center and at the surrounding ring. These spatially separate regions of PBP2x activity could not be detected by previous activity-based approaches, which highlights a critical strength of our PBP-selective imaging strategy."

lactones identified as a privileged scaffold for the generation of PBP-selective probes and these compounds were used for imaging of the essential proteins, PBP2x and PBP2b, in Streptococcus pneumoniae

In addition to Professor Carlson, authors of the article were Shabnam Sharifzadeh, Alireza Shokri, and Joshua Shirley from the departments of Chemistry, Medicinal Chemistry, and Biochemistry, Molecular Biology and Biophysics at the University of Minnesota, and Ozden Kocaoglu, Michael J. Boersma∥, Ozden Kocaoglu, Clayton L. Brown, and Malcolm E. Winkler from the departments of Biology, Molecular and Cellular Biochemistry, and Chemistry at Indiana University.