skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

This content will become publicly available on October 24, 2019

Title: The structures of penicillin-binding protein 4 (PBP4) and PBP5 from Enterococci provide structural insights into β-lactam resistance

Abstract

The final steps of cell-wall biosynthesis in bacteria are carried out by penicillin-binding proteins (PBPs), whose transpeptidase domains form the cross-links in peptidoglycan chains that define the bacterial cell wall. These enzymes are the targets of β-lactam antibiotics, as their inhibition reduces the structural integrity of the cell wall. Bacterial resistance to antibiotics is a rapidly growing concern; however, the structural underpinnings of PBP-derived antibiotic resistance are poorly understood. PBP4 and PBP5 are low-affinity, class B transpeptidases that confer antibiotic resistance to Enterococcus faecalis and Enterococcus faecium, respectively. We report the crystal structures of PBP4 (1.8 Å) and PBP5 (2.7 Å) in their apo and acyl-enzyme complexes with the β-lactams benzylpenicillin, imipenem, and ceftaroline. We found that, although these three β-lactams adopt geometries similar to those observed in other class B PBP structures, there are small, but significant, differences that likely decrease antibiotic efficacy. Further, we also discovered that the N-terminal domain extensions in this class of PBPs undergo large rigid-body rotations without impacting the structure of the catalytic transpeptidase domain. Together, our findings are defining the subtle functional and structural differences in the Enterococcus PBPs that allow them to support transpeptidase activity while also conferring bacterial resistance to antibioticsmore » that function as substrate mimics.« less

Authors:
ORCiD logo [1];  [1];  [2];  [3];  [3];  [4];  [4];  [4];  [1];  [1]
  1. Univ. of Arizona, Tucson, AZ (United States). Dept. of Chemistry and Biochemistry. College of Medicine
  2. Brown Univ., Providence, RI (United States). Dept. of Molecular Pharmacology, Physiology, and Biotechnology
  3. Brookhaven National Lab. (BNL), Upton, NY (United States). Photon Sciences
  4. Brown Univ., Providence, RI (United States). Dept. of Medicine. Dept. of Microbiology and Immunology. Warren Alpert School of Medicine
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States); Univ. of Arizona, Tucson, AZ (United States); Brown Univ., Providence, RI (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Inst. of Health (NIH) (United States)
OSTI Identifier:
1502803
Report Number(s):
BNL-211431-2019-JAAM
Journal ID: ISSN 0021-9258
Grant/Contract Number:  
SC0012704; AC02-76SF00515; P41GM103393; R56AI045626
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 293; Journal Issue: 48; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; crystal structure; Enterococcus; antibiotic action; antibiotic resistance; enzyme structure; penicillin-binding proteins; transpeptidase; β-lactam; ESKAPE pathogen

Citation Formats

Moon, Thomas M., D'Andréa, Éverton D., Lee, Christopher W., Soares, Alexei, Jakoncic, Jean, Desbonnet, Charlene, Garcia-Solache, Monica, Rice, Lou B., Page, Rebecca, and Peti, Wolfgang. The structures of penicillin-binding protein 4 (PBP4) and PBP5 from Enterococci provide structural insights into β-lactam resistance. United States: N. p., 2018. Web. doi:10.1074/jbc.RA118.006052.
Moon, Thomas M., D'Andréa, Éverton D., Lee, Christopher W., Soares, Alexei, Jakoncic, Jean, Desbonnet, Charlene, Garcia-Solache, Monica, Rice, Lou B., Page, Rebecca, & Peti, Wolfgang. The structures of penicillin-binding protein 4 (PBP4) and PBP5 from Enterococci provide structural insights into β-lactam resistance. United States. doi:10.1074/jbc.RA118.006052.
Moon, Thomas M., D'Andréa, Éverton D., Lee, Christopher W., Soares, Alexei, Jakoncic, Jean, Desbonnet, Charlene, Garcia-Solache, Monica, Rice, Lou B., Page, Rebecca, and Peti, Wolfgang. Wed . "The structures of penicillin-binding protein 4 (PBP4) and PBP5 from Enterococci provide structural insights into β-lactam resistance". United States. doi:10.1074/jbc.RA118.006052.
@article{osti_1502803,
title = {The structures of penicillin-binding protein 4 (PBP4) and PBP5 from Enterococci provide structural insights into β-lactam resistance},
author = {Moon, Thomas M. and D'Andréa, Éverton D. and Lee, Christopher W. and Soares, Alexei and Jakoncic, Jean and Desbonnet, Charlene and Garcia-Solache, Monica and Rice, Lou B. and Page, Rebecca and Peti, Wolfgang},
abstractNote = {The final steps of cell-wall biosynthesis in bacteria are carried out by penicillin-binding proteins (PBPs), whose transpeptidase domains form the cross-links in peptidoglycan chains that define the bacterial cell wall. These enzymes are the targets of β-lactam antibiotics, as their inhibition reduces the structural integrity of the cell wall. Bacterial resistance to antibiotics is a rapidly growing concern; however, the structural underpinnings of PBP-derived antibiotic resistance are poorly understood. PBP4 and PBP5 are low-affinity, class B transpeptidases that confer antibiotic resistance to Enterococcus faecalis and Enterococcus faecium, respectively. We report the crystal structures of PBP4 (1.8 Å) and PBP5 (2.7 Å) in their apo and acyl-enzyme complexes with the β-lactams benzylpenicillin, imipenem, and ceftaroline. We found that, although these three β-lactams adopt geometries similar to those observed in other class B PBP structures, there are small, but significant, differences that likely decrease antibiotic efficacy. Further, we also discovered that the N-terminal domain extensions in this class of PBPs undergo large rigid-body rotations without impacting the structure of the catalytic transpeptidase domain. Together, our findings are defining the subtle functional and structural differences in the Enterococcus PBPs that allow them to support transpeptidase activity while also conferring bacterial resistance to antibiotics that function as substrate mimics.},
doi = {10.1074/jbc.RA118.006052},
journal = {Journal of Biological Chemistry},
number = 48,
volume = 293,
place = {United States},
year = {2018},
month = {10}
}

Journal Article:
Free Publicly Available Full Text
This content will become publicly available on October 24, 2019
Publisher's Version of Record

Save / Share:

Works referenced in this record:

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunk�czi, G�bor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925