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Conformational analysis of bacterial cell wall peptides indicates how particular conformations have influenced the evolution of penicillin‐binding proteins, β‐lactam antibiotics and antibiotic resistance mechanisms
Author(s) -
Grail Barry M.,
Payne John W.
Publication year - 2002
Publication title -
journal of molecular recognition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.401
H-Index - 79
eISSN - 1099-1352
pISSN - 0952-3499
DOI - 10.1002/jmr.566
Subject(s) - penicillin binding proteins , chemistry , peptide , stereochemistry , conformational isomerism , cell wall , lactam , bacterial cell structure , protein structure , beta sheet , side chain , peptidoglycan , antibiotics , biophysics , penicillin , biochemistry , molecule , bacteria , biology , organic chemistry , genetics , polymer
Our aim was to use a conformational analysis technique developed for peptides to identify structural relationships between bacterial cell wall peptides and β‐lactam antibiotics that might help to explain their different actions as substrates and inhibitors of penicillin binding proteins (PBPs). The conformational forms of the model cell wall peptide Ac‐ L ‐Lys(Ac)‐ D ‐Ala‐ D ‐Ala are described by just a few backbone torsion combinations: three C‐terminal carboxylate regions, with Tor8 (ψ i+1 ) ranges of D3 region (50° to 70°), D6 region (140° to 170°) and D9 region (−50° to −70°) are combined with either of two Tor6 (ϕ i )‐Tor4 (ψ i ) combinations, C4 region (−50° to −80°) with B8 region (−40° to −70°) or C11 region (30° to 50°) with B2 region (30° to 70°). From these results, and comparisons with conformational analyses of various β‐lactams and Ac‐ L ‐Lys(Ac)‐ D ‐Ala‐ D ‐Lac, it is concluded that molecular recognition of cell wall peptide substrates by PBPs requires conformers with backbone torsion angles of D3C4B8. β‐Lactam antibiotics are constrained compounds with fewer conformational forms; these match well the backbone torsions of cell wall peptides at D3C4, allowing their recognition and acylation by PBPs, whereas their unique Tor4 produces differently orientated CO and N atoms that appear to prevent subsequent deacylation, leading to their action as suicide substrates. The results are also related to the selective pressures involved in evolution of β‐lactamases from PBPs. From analysis of conformers of Ac‐ L ‐Lys(Ac)‐ D ‐Ala‐ D ‐Ala and the vancomycin‐resistant analogue Ac‐ L ‐Lys(Ac)‐ D ‐Ala‐ D ‐Lac, it is concluded that vancomycin may recognise D6C11B2 conformers, giving it complementary substrate specificity to PBPs. This approach could have applications in the rational design of antibiotics targeted against PBPs and their substrates. Copyright © 2002 John Wiley & Sons, Ltd.