One ring to rule them all: Current trends in combating bacterial resistance to the β-lactams

Abstract

From humble beginnings of a contaminated petri dish, β-lactam antibiotics have distinguished themselves among some of the most powerful drugs in human history. The devastating effects of antibiotic resistance have nevertheless led to an "arms race" with disquieting prospects. The emergence of multidrug resistant bacteria threatens an ever-dwindling antibiotic arsenal, calling for new discovery, rediscovery, and innovation in β-lactam research. Here the current state of β-lactam antibiotics from a structural perspective was reviewed.

Keywords: multidrug resistant bacteria; penicillin-binding protein; resistance; β-lactam; β-lactamase.

Figure 1

The chemical structure of benzylpenicillin and various β‐lactamase inhibitors.

Figure 2

SBL inhibitors. (A) CTX‐M‐15 inhibition by avibactam. In the left panel is a general reaction scheme for the formation of an avibactam carbamyl‐enzyme intermediate. In the right panel is an active site close‐up of the carbamyl avibactam‐CTX‐M‐15 complex (PDB ID: 4HBU). The CTX‐M‐15 protein backbone is illustrated in green cartoon representation and the bound avibactam is shown as pink sticks. (B) Bacillus licheniformis BS3 inhibition by clavulanic acid. A general reaction scheme for clavulanic acid mediated SBL acylation is shown in the left panel. In the right panel is an active site close‐up of the acyl clavulanic acid‐BS3 complex (PDB ID: 2Y91). The BS3 protein backbone is displayed as a beige cartoon and clavulanic acid is represented as pink sticks. (C) Toho‐1 inhibition by the boronic acid based inhibitor BZB. In the left panel is a general reaction scheme for the formation of the SBL bound tetrahedral boron adduct. In the right panel is an active site close‐up of the tetrahedral BZB boronate adduct bound to the Toho‐1 catalytic serine (PDB ID: 4BD0). The Toho‐1 protein chain and bound BZB are displayed as an orange cartoon and pink sticks. In A–C, key active site residues are displayed in stick representation with all non‐carbon atoms colored by type (N; blue, O; red, S; yellow, B; beige). Hydrogen bonding interactions are represented as black dashes.

Figure 3

Inhibition of the S. aureus PBP2a by Ceftobiprole. (A) Kinetic model for PBP inhibition by β‐lactams. (B) General model for SBL mediated ceftobiprole acylation. (C) Active site close‐up of acyl‐ceftobiprole bound S. aureus PBP2a (PDB ID: 4DKI). The acyl‐enzyme protein chain is displayed as a teal cartoon with key active site residues shown in stick representation with atoms colored by type. (D) Active site overlay of unbound (PDB ID: 1VQQ) and ceftobiprole bound S. aureus PBP2a. The bound and unbound protein backbones are shown as teal and yellow cartoons with key active site residues illustrated in stick representation with non‐carbon atoms colored according to atom type. In C and D, the bound ceftobiprole is shown in pink sticks with atoms colored by type and hydrogen‐bonding interactions are depicted as black dashes.

Figure 4

Inhibition of the S. aureus PBP2a by ceftaroline. (A) General model for ceftaroline mediated PBP acylation. (B) Structural details of ceftaroline mediated PBP2a inhibition. On the left, the overall ceftaroline bound PBP2a protein structure (PDB ID: 3ZG0) is shown in surface representation with the N‐terminal extension, allosteric domain, and TPase domain colored green, yellow, and cyan. On the right side are close‐up views of the ceftaroline bound allosteric and TPase domains with the protein chain depicted in cartoon representation and key residues shown as sticks with non‐carbon atoms colored by atom type. Ceftaroline is shown as pink sticks.

Figure 5

Representative β‐lactam uptake and efflux systems in Gram‐negative E. coli. β‐Lactams enter the periplasm through outer membrane porins such as OmpF (PDB ID 2ZFG), where they inhibit periplasmic PBP targets. Dianionic β‐lactams such as carbenicillin can be expelled from the cell via RND efflux pumps, represented by the AcrAB‐TolC complex (PDB ID 2F1M, 1OYE, 1EK9), where the drug is captured from the periplasmic or periplasmic‐cytoplasmic interface. Siderophore conjugated β‐lactam drugs can use cognate siderophore receptors for entry as represented here by FhuA complexed with TonB/ExbB/ExbD (FhuA and C‐terminus of TonB: PDB ID 2GRX; ExbD: PDB ID 2PFU). The TonB complex couples the proton motive force across the inner membrane to facilitate the active transport mechanism of FhuA across the outer membrane.