Resistance to β -lactam antibiotics by re-modelling the active site of an E. coli penicillin-binding protein

• Published in: Nature (London) 1985-12, Vol.318 (6045), p.478-480
• Main Authors: Hedge, Philip J, Spratt, Brian G
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacterial Proteins; beta-Lactams; Binding Sites; Biological and medical sciences; Carboxypeptidases - analysis; Carrier Proteins - analysis; Drug Resistance, Microbial; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - metabolism; Hexosyltransferases; Humanities and Social Sciences; letter; Medical sciences; multidisciplinary; Muramoylpentapeptide Carboxypeptidase - analysis; Mutation; Penicillin-Binding Proteins; Peptidyl Transferases; Pharmacology. Drug treatments; Science
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/318478a0

The β -lactam antibiotics kill bacteria by inhibiting a set of penicillin-binding proteins (PBPs) that catalyse the final stages of peptidoglycan synthesis 1,2 . In some bacteria the development of intrinsic resistance to β -lactam antibiotics by the reduction in the affinity of PBPs causes serious clinical problems 1,3–11 . The introduction of β -lactam antibiotics that are resistant to hydrolysis by β -lactamases may also result in the emergence of intrinsic resistance among the Enterobacteriaceae 1 . The clinical problems that would arise from the emergence of resistant PBPs in enterobacteria have led us to examine the ease with which Escherichia coli can gain resistance to β -lactams by the production of altered PBPs. The development of resistant PBPs also provides an interesting example of enzyme evolution, since it requires a subtle re-modelling of the enzyme active centre so that it retains affinity for its peptide substrate but excludes the structurally analogous 2,12,13 β -lactam antibiotics. We show here that only four amino-acid substitutions need to be introduced into PBP 3 of E. coli to produce a strain possessing substantial levels of resistance to a wide variety of cephalosporins. We also show that transfer of the gene encoding the resistant PBP 3 from the chromosome to a plasmid could result in the spread of intrinsic resistance not only to other strains of E. coli but also to other enterobacterial species.