Chapter 3 : Antibiotics That Act on Cell Wall Biosynthesis

Antibiotics that act on cell wall biosynthesis.

Cell wall structures of gram-positive and gram-negative bacteria: (A) differences in outer membrane permeability barriers; (B) peptidoglycan elongation by transglycosylase action; (C) peptidoglycan cross-linking by transpeptidase action; (D) penetration of antibiotics to the cytoplasmic membrane in gram-positive bacteria.

Cell walls of bacteria. (A and B) Schematic diagrams of gram-positive (A) and gram-negative (B) cell walls. (C and D) Electron micrographs showing the cell walls of a gram-positive bacterium, Arthrobacter crystallopoietes (C), and a gram-negative bacterium, Leucothrix mucor (D). (E and F) Scanning electron micrographs of gram-positive (Bacillus subtilis) (E) and gram-negative (Escherichia coli) (F) bacteria. Note the surface texture in the cells shown in panels E and F. A single cell of B. subtilis or E. coli is about 1 mm in diameter.

Action of cell wall transglycosylases on the C55-lipid-linked N-acetyl-muramyl (MurNAc) pentapeptide substrate.

Assembly of UDP-MurNAc pentapeptide by the six enzymes MurA-F.

(A) Sequential action of MurA and MurB to convert UDP-N-acetyl-glucosamine (GlcNAc) to UDP-N-MurNAc. (B) Inactivation of MurA by the antibiotic fosfomycin.

Conversion of UDP-MurNAc to UDP-MurNAc tripeptide by action of MurC, D, and E.

(A) Aminoacyl-phosphate generation. (B) MurC example with UDP-MurNAc-P as a bound intermediate attacked by the amino group of cosubstrate l-Ala. (C) UDP-tripeptidyl acyl-P intermediate in MurF catalysis: attack by d-Ala-D-Ala.

(A) Sequential action of alanine racemase and d-Ala-d-Ala ligase (Ddl) to generate d-Ala-d-Ala. (B) d-Ala-P intermediate in Ddl catalysis.

(A) Enzymatic formation of the lipid I and lipid II intermediates in the membrane phase of peptidoglycan assembly. (B) Nucleoside-peptide inhibitors of MraY.

The lipid carrier cycle in peptidoglycan assembly. TGase, transglycosylase; PPiase, pyrophosphatase.

Structures of two antibiotics that form stoichiol metric complexes with lipid II: (A) ramoplanin; (B) mersacidin.

Bacitracin and a model for complexation of the C55 lipid phosphate to block the lipid cycle.

Schematic of a multi-enzyme complex involved in traveling along the peptidoglycan scaffold during elongation. TG, transglycosylase; TP, transpeptidase; TP/TG, Bi-functional transpeptidase / transglycosylase; EP, endopeptidase; LT, lytic transglycosylase. (Adapted from Holtje [1998], with permission.)

β-Lactam antibiotics: (A) penicillins, (B) cephalosporins, (C) carbapenems, (D) monobactams, and (E) clavams.

Mechanism of the PG transpeptidation reaction to create the DAP-d-Ala isopeptide bond: acyl enzyme intermediate in transpeptidase action. (A) Acyl enzyme formation; (B) acyl enzyme deacylation and capture by the amine nucleophile of a neighboring chain.

Reaction of penicillin as a suicide substrate for PG transpeptidases.

Multiple penicillin-binding proteins in E. coli: auto-radiographs of 14C-penicilloylproteins of E. coli separated on denaturing gel electrophoresis. (From Dougherty et al. [1996], with permission.)

Different generations of (A) penicillins and (B) cephalosporins. (Adapted from Scholar and Pratt [2000], with permission.)

Different generations of (A) penicillins and (B) cephalosporins. (Adapted from Scholar and Pratt [2000], with permission.)

Structures of the glycopeptide antibiotics vancomycin and teicoplanin.

Sequestration of PG-d-Ala-d-Ala termini by vancomycin. (A) Five hydrogen bonds between the antibiotic and PG terminus; (B) space-filling model of the antibiotic and PG terminus.

PG termini interacting with vancomycin and teicoplanin: (A) un-cross-linked strands on preexisting PG; (B) the lipid II substrate before polymerization into PG.

Model for moenomycin interaction with target transglycosylases. (From Kurz et al. [1998], with permission.)