Structural Insights for β-Lactam Antibiotics

Abstract

Antibiotic resistance has emerged as a global threat to modern healthcare systems and has nullified many commonly used antibiotics. β-Lactam antibiotics are among the most successful and occupy approximately two-thirds of the prescription antibiotic market. They inhibit the synthesis of the peptidoglycan layer in the bacterial cell wall by mimicking the D-Ala-D-Ala in the pentapeptide crosslinking neighboring glycan chains. To date, various β-lactam antibiotics have been developed to increase the spectrum of activity and evade drug resistance. This review emphasizes the three-dimensional structural characteristics of β-lactam antibiotics regarding the overall scaffold, working mechanism, chemical diversity, and hydrolysis mechanism by β-lactamases. The structural insight into various β-lactams will provide an in-depth understanding of the antibacterial efficacy and susceptibility to drug resistance in multidrug-resistant bacteria and help to develop better β-lactam antibiotics and inhibitors.

Keywords: Antibiotic resistance; Antibiotics; Metallo-β-lactamases; Peptidoglycan; Serine β-lactamases; β-Lactams.

Fig. 1

Schematic drawings of representative peptidoglycan layers and D-Ala-D-Ala and β-lactams. (A) The representative structure of the peptidoglycan of E. coli. The glycan strands consist of alternating β(1→4) linked GlcNAc and MurNAc residues. Each MurNAc residue has a pentapeptide stem whose composition is most often L-Ala₁-D-Glu₂-mDAP₃-D-Ala₄-D-Ala₅. The terminal residues of the D-Ala₄-D-Ala₅ dipeptide are marked as magenta and cyan, respectively. (B) The core chemical structures of the D-Ala-D-Ala dipeptide part and four major classes of β-lactams of penicillin, cephalosporin, carbapenem, and monobactam. Structurally corresponding parts in the D-Ala-D-Ala and β-lactams are marked in the same colors as (A). The additional chemical R parts attached to the D-Ala₄ or β-lactam ring are shaded in red, and those to the D-Ala₅ or other ring are in blue.

Fig. 2

The structural comparisons of the D-Ala-D-Ala and three β-lactam antibiotics. (A) The crystal structure of D-Ala-D-Ala (PDB ID: 3ITB) is labeled with the constituting two angles and a dihedral angle. The three-dimensional modeled structures (left) of (B) ampicillin, (C) cefotaxime, and (D) imipenem with the superimposed structures (right) to D-Ala-D-Ala. (E) The top view shows the bent angle between two rings of the ampicillin core scaffold. The convex side of ampicillin is labeled as a black line, and the direction of nucleophilic attack on the β-lactam ring by penicillin-binding proteins (PBPs) or β-lactamases is shown as a black arrow. Structurally corresponding parts in the D-Ala-D-Ala and β-lactams are marked in the same colors as Fig. 1.

Fig. 3

The intermediate catalytic structures of penicillin-binding proteins, a serine β-lactamase, and a metallo-β-lactamase in complex with the D-Ala-D-Ala analogs and penicillin G and schematic representations of catalytic mechanisms. (A) The crystal structures of D-Ala-D-Ala-mimicking substrates and a catalytic serine residue of before (PDB ID: 3ITB) and after (PDB ID: 2J9P) nucleophilic attack on the D-Ala₄ in penicillin-binding proteins. (B) The crystal structure of hydrolyzed penicillin G attached to the catalytic serine of serine β-lactamase OXA-10 (PDB ID: 2WGI). (C) The crystal structure of hydrolyzed penicillin G with the zinc ions from metallo-β-lactamase NDM-1 (PDB ID: 4RAM). The proposed position of a catalytic water molecule is labeled with a dotted red circle. Structurally corresponding parts in the D-Ala-D-Ala and β-lactams are marked in the same colors as Fig. 1.

Fig. 4

The chemical structures of four main classes of β-lactam antibiotics. The conserved core scaffolds of each class of β-lactam antibiotics and the chemical structures of belonging members. The modification moieties attached to the β-lactam ring are shaded in red, and those at the other ring in blue are shown in Fig. 1.