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

Journal Article · · Journal of Biological Chemistry
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
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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.

Research Organization:
Brookhaven National Lab. (BNL), Upton, NY (United States); Univ. of Arizona, Tucson, AZ (United States); Brown Univ., Providence, RI (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Inst. of Health (NIH) (United States)
Grant/Contract Number:
SC0012704; AC02-76SF00515; P41GM103393; R56AI045626
OSTI ID:
1502803
Report Number(s):
BNL-211431-2019-JAAM
Journal Information:
Journal of Biological Chemistry, Vol. 293, Issue 48; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 23 works
Citation information provided by
Web of Science

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Cited By (2)

Structural basis for the coordination of cell division with the synthesis of the bacterial cell envelope journal September 2019
Inhibiting the copper efflux system in microbes as a novel approach for developing antibiotics journal December 2019

Figures / Tables (7)

Table 1(p. 21)table Table 1
Table 2(p. 22)table Table 2
Table 3(p. 24)table Table 3
Figure 1(p. 28)figure Figure 1
Figure 2(p. 29)figure Figure 2
Figure 3(p. 30)figure Figure 3
Figure 4(p. 31)figure Figure 4

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Related Subjects

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