Penicillins and Cell-Wall-Synthesis Inhibitors

Penicillins and Cell-Wall-Synthesis Inhibitors

1. Definition, scope & the cell-wall target

• The bacterial cell envelope (inner/plasma membrane, cell wall, and — in gram-negatives — an outer membrane) is a key target for several antibacterial classes: β-lactams, glycopeptides, lipopeptides, and minor agents such as bacitracin and the polymyxins (the last discussed with the miscellaneous agents, not here) (G&G 14e Ch.58, p.1147).
• Cell-wall-synthesis inhibitors are the antimicrobials that block assembly of the bacterial peptidoglycan (murein) cell wall — a heteropolymer that provides the rigid mechanical stability the cell needs against its own high internal osmotic pressure (G&G 14e Ch.58, p.1147; KDT 8e Ch.52, p.766).
• The β-lactam antibiotics — penicillins, cephalosporins, carbapenems, and monobactams — share a common β-lactam ring and a common mechanism (inhibition of peptidoglycan cross-linking); they are "the single most important antibacterial class" given broad spectrum, potent bactericidal killing, and generally favourable tolerability (G&G 14e Ch.58, p.1147).
• Non-β-lactam cell-wall agents covered here: the glycopeptides (vancomycin, teicoplanin) and lipoglycopeptides (telavancin, dalbavancin, oritavancin), the lipopeptide daptomycin (membrane target, strictly speaking, not wall synthesis), and bacitracin (G&G 14e Ch.58, pp.1160–1162).
• Scope note: Cephalosporins have their own dedicated topic and are treated only in overview here for completeness of the β-lactam family; the penicillins and the non-β-lactam wall agents are the focus of this account.

Peptidoglycan biosynthesis (the pathway β-lactams and vancomycin attack)

• Peptidoglycan is composed of glycan chains — linear strands of two alternating amino sugars, N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) — that are cross-linked by short peptide chains (G&G 14e Ch.58, p.1147).
• Precursor formation begins in the cytoplasm: synthesis of UDP–N-acetylmuramyl-pentapeptide is completed by adding the dipeptide d-alanyl-d-alanine, itself formed by racemisation and condensation of l-alanine (G&G 14e Ch.58, p.1147).
• KDT names the cytoplasmic precursor the "Park nucleotide" (UDP-N-acetylmuramic acid pentapeptide) — so called because Park (1957) found it to accumulate when susceptible Staphylococcus was grown in the presence of penicillin (KDT 8e Ch.52, p.766).
• UDP-acetylmuramyl-pentapeptide and UDP-acetylglucosamine are linked (transglycosylation) with release of the uridine nucleotides to form a long glycan polymer; the disaccharide-pentapeptide subunits are ferried across the membrane on the lipid carrier bactoprenol (lipid II) (G&G 14e Ch.58, p.1147; KDT 8e Ch.52, p.767).
• The final, extracytoplasmic step is the transpeptidation cross-link: a transpeptidase cleaves the terminal d-alanine of one pentapeptide and forms a peptide cross-bridge to the adjacent strand (in S. aureus, a (Gly)₅ bridge between lysines), using the energy released; this cross-linking gives the wall its rigidity (G&G 14e Ch.58, p.1147–1149; KDT 8e Ch.52, pp.766–767).
• Gram-positive wall is 50–100 molecules thick, almost entirely peptidoglycan, extensively cross-linked (effectively one giant mucopeptide molecule); gram-negative wall is only 1–2 molecules thick with little cross-linking, sandwiched between inner and outer membranes — this architecture underlies much of the differential susceptibility to penicillin G (G&G 14e Ch.58, p.1147; KDT 8e Ch.52, pp.767–768).
• The peptidoglycan wall (and specifically the use of d-alanine) is unique to bacteria and not made by higher animals — the basis of the selective toxicity and near-nontoxicity of penicillin to humans (KDT 8e Ch.52, p.768).