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Expanded profiling of β-lactam selectivity for penicillin-binding proteins in Streptococcus pneumoniae D39

  • Deepti Sharan and Erin E. Carlson ORCID logo EMAIL logo
Published/Copyright: February 28, 2022
Biological Chemistry
From the journal Biological Chemistry Volume 403 Issue 4

Abstract

Penicillin-binding proteins (PBPs) are integral to bacterial cell division as they mediate the final steps of cell wall maturation. Selective fluorescent probes are useful for understanding the role of individual PBPs, including their localization and activity during growth and division of bacteria. For the development of new selective probes for PBP imaging, several β-lactam antibiotics were screened, as they are known to covalently bind PBP in vivo. The PBP inhibition profiles of 16 commercially available β-lactam antibiotics were evaluated in an unencapsulated derivative of the D39 strain of Streptococcus pneumoniae, IU1945. These β-lactams have not previously been characterized for their PBP inhibition profiles in S. pneumoniae and these data augment those obtained from a library of 20 compounds that we previously reported. We investigated seven penicillins, three carbapenems, and six cephalosporins. Most of these β-lactams were found to be co-selective for PBP2x and PBP3, as was noted in our previous studies. Six out of 16 antibiotics were selective for PBP3 and one molecule was co-selective for PBP1a and PBP3. Overall, this work expands the chemical space available for development of future β-lactam-based probes for specific pneumococcal PBP labeling and these methods can be used for the development of probes for PBP labelling in other bacterial species.

Keywords: β-lactams; activity-based probes; antibiotics; penicillin-binding proteins
Corresponding author: Erin E. Carlson, Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN 55455, USA; Department of Medicinal Chemistry, University of Minnesota, 208 Harvard Street SE, Minneapolis, MN 55454, USA; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 321 Church St SE, Minneapolis, MN 55454, USA; and Department of Pharmacology, University of Minnesota, 321 Church St SE, Minneapolis, MN 55454, USA, E-mail:

Funding source: University of Minnesota

Award Identifier / Grant number: Unassigned

Funding source: National Institutes of Health

Award Identifier / Grant number: GM140486-01

Acknowledgments

The authors thank the Malcolm Winkler Lab at Indiana University for providing S. pneumoniae strains, and the rest of the Carlson Lab for helpful discussion and support. This work was supported by the National Institutes of Health (GM140486-01) and the University of Minnesota, Department of Chemistry.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: National Institutes of Health (GM140486-01) and the University of Minnesota, Department of Chemistry.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2021-0386).

Received: 2021-10-06
Revised: 2022-01-31
Accepted: 2022-02-10
Published Online: 2022-02-28
Published in Print: 2022-03-28

© 2022 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/hsz-2021-0386
Keywords for this article
β-lactams; activity-based probes; antibiotics; penicillin-binding proteins

Articles in the same Issue

  1. Frontmatter
  2. Highlight: Chemical Biology in Drug Discovery
  3. Chemical biology in drug discovery
  4. Rational approaches towards inorganic and organometallic antibacterials
  5. Epithelial-mesenchymal transition and H2O2 signaling – a driver of disease progression and a vulnerability in cancers
  6. Covalent fragment-based ligand screening approaches for identification of novel ubiquitin proteasome system modulators
  7. Artificial metalloenzymes in a nutshell: the quartet for efficient catalysis
  8. Photochemical protein modification in complex biological environments: recent advances and considerations for future chemical methods development
  9. Using the yeast three-hybrid system for the identification of small molecule-protein interactions with the example of ethinylestradiol
  10. Expanded profiling of β-lactam selectivity for penicillin-binding proteins in Streptococcus pneumoniae D39
  11. Two-photon fluorescent turn-on probes for highly efficient detection and profiling of thiols in live cells and tissues
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