bacterial cell wall synthesis & inhibitors

What is peptidoglycan?

Large cross-linked polymer (murein) giving bacterial cell wall rigidity; absent in mammalian cells → selective toxicity target

What are the two amino sugar monomers in peptidoglycan?

N-acetylglucosamine (NAG); N-acetylmuramic acid (NAM)

What is attached to NAM?

Pentapeptide ending in two D-alanine residues; one D-alanine cleaved during cross-linking

Third amino acid in NAM-pentapeptide — Gram-positive vs Gram-negative?

Gram-positive = L-lysine; Gram-negative = meso-diaminopimelic acid (mDap)

Peptidoglycan amount & cross-linking — Gram-positive vs Gram-negative?

Gram-positive = thick layer, often pentaglycine bridges; Gram-negative = thin layer, direct cross-links plus outer membrane

Three principal stages of peptidoglycan synthesis?

1) Cytoplasm — make NAG–NAM–pentapeptide monomer; 2) Membrane transport — carry monomer across via lipid carrier; 3) Cell wall — polymerisation + cross-linking

How is NAM formed?

NAG + phosphoenolpyruvate (PEP) → add lactic acid → NAM; blocked by fosfomycin

How is the NAM-pentapeptide completed?

Add L-ala, D-glu, L-lys/mDap; L-ala → D-ala via racemase; two D-ala added by ligase; blocked by D-cycloserine

Lipid carrier for transport?

Bactoprenol; binds NAG–NAM–pentapeptide, flips across membrane, delivers to cell wall, recycled

Enzyme linking monomers into glycan chains?

Glycosyltransferase / transglycosylase; builds polymer chains; blocked by glycopeptides

Enzyme cross-linking peptidoglycan chains?

Transpeptidase / penicillin-binding protein (PBP); cleaves terminal D-ala to power bond formation; inhibited by all β-lactams

Result of blocked peptidoglycan synthesis?

Cell wall weakens → leaky → swelling → osmotic lysis → bactericidal action

Fosfomycin — mechanism & use?

PEP analogue; blocks NAG→NAM conversion; used mainly for urinary tract infections (Gram-negatives)

D-Cycloserine — mechanism & use?

D-alanine analogue; inhibits racemase (L-ala→D-ala) & ligase (D-ala–D-ala addition); second-line for tuberculosis

Glycopeptides — examples, mechanism & spectrum?

Vancomycin, teicoplanin; bind D-ala–D-ala terminus → block transglycosylase; Gram-positive only (too large for Gram-negative outer membrane); used for MRSA, C. difficile

Shared mechanism of all β-lactams?

Mimic D-ala–D-ala; bind & inactivate transpeptidase/PBP; cross-linking fails → autolysins cause lysis → bactericidal

Four β-lactam subclasses?

Penicillins; Cephalosporins; Carbapenems; Monobactams

Penicillins — spectrum & resistance note?

Hydrophilic (amoxicillin, ampicillin) = broad; hydrophobic (penicillin G/V, flucloxacillin) = narrow; resistance mainly via β-lactamase enzymes

Cephalosporins — key feature?

Grouped by generations; activity shifts from Gram-positive → Gram-negative; better β-lactamase stability

Carbapenems — key feature?

Broadest spectrum; stable against most β-lactamases; not active against MRSA; used for severe/hospital infections

Monobactams — example & spectrum?

Aztreonam; active only against Gram-negatives; safe in penicillin-allergic patients

Why are cell wall inhibitors selectively toxic?

Human cells have no cell wall → no target exists → high therapeutic index

Vancomycin — why inactive against Gram-negatives?

Large molecule cannot penetrate the Gram-negative outer membrane

Hydrophilic vs hydrophobic β-lactams — spectrum difference?

Hydrophilic pass through porins in Gram-negative outer membrane → broader coverage; hydrophobic penetrate poorly → mainly Gram-positive

Match drug to step blocked — cytoplasm to cell wall?

Fosfomycin = NAG→NAM; D-Cycloserine = D-ala synthesis/ligase; Glycopeptides = transglycosylase (chain extension); β-lactams = transpeptidase (cross-linking)