Researchers Zoom in on Penicillin-Binding Protein

Researchers have succeeded in reaching a resolution of 1.8 angstroms for the crystal structure of a soluble derivative of penicillin-binding protein (PBP2a), the transpeptidase enzyme responsible for antibiotic resistance in Staphylococcus aureus. Their work was reported in the October 21, 2002, online edition of Nature Structural Biology.

Resistant strains of S aureus comprise 34% of the clinical isolates in the United States, more than 60% in Japan, Singapore and Taiwan, and more than 50% in Italy and Portugal. Some strains of S aureus known as MRSA (methicillin-resistant S aureus) became resistant to most beta-lactam antibiotics when they acquired the gene for PBP2a. Because of its low affinity for beta-lactams, PBP2a provides transpeptidase activity to allow cell wall synthesis at beta-lactam concentrations that inhibit the beta-lactam-sensitive PBPs normally produced by S aureus.

To understand the detailed structure of PBP2a, researchers at the University of British Columbia (Canada) produced a soluble version that lacked the segment that anchored the protein to the cell membrane, but which retained its enzymatic activity. This allowed study by x-ray crystallography, which revealed critical differences between the structures of PBP2a and other beta-lactam antibiotic sensitive PBPs.

"By comparing the native enzyme with previously known structures of transpeptidases, we came to understand that PBP2a had evolved distortions of the active site that prevent an effective reaction with the antibiotic,” explained senior author Dr. Natalie Strynadka. "Although beta-lactam-sensitive bacteria still have a number of these normal transpeptidases, they also have PBP2a, which because of its distorted active site does not react easily with the antibiotic. Thus, PBP2a can produce sufficient cross-linking in the cell wall so that the bacterium survives.”




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