Chemotherapeutic Antibiotics: Cell Wall Inhibition (DONE) Flashcards
Why is there a need for new antibiotics?
Only 10-15 targets
Resistance is inevitable and now a major concern
Peptidoglycan in cell wall synthesis
Peptidoglycan is an essential wall polymer, responsible for shape and integrity, unique in prokaryotes
Interference with its synthesis or structure leads to loss of cell shape and integrity followed by bacterial death
What is peptidoglycan made of?
Contains chains of alternating N-acetylmuramic acid and N-acetylglucosamine residues, cross-linked through pentapeptide side chains attached to MurNAc
The pentapeptide side chain sequence is L-Ala (occasionally L-Gly): D-Glu-X-D-Ala-D-Ala
Where X is usually a diamino acid and most often meso-diaminopimelic acid or L-Lys
Biosynthesis of peptidoglycan (overview)
Synthesis of precursors in the cytoplasm, or at the inner surface of the cytoplasmic membrane
Transfer across the cytoplasmic membrane
Polymerization on the outer surface
Cell wall synthesis stage 1
Assembly of the disaccharide-peptide monomer unit by enzymes located in the cytoplasm, or at the inner surface of the cytoplasmic membrane
Synthesis of cytoplasmic cell wall precursors
Cell wall synthesis stage 2
Transfer of the monomer unit across the cytoplasmic membrane
Synthesis of wall subunit attached to lipid carriers
Cell wall synthesis stage 3
Polymerization of the monomer unit on the outer surface of the membrane and concomitant binding of the nascent peptidoglycan to the pre-existing cell wall
Polymerisation of glycan and attachment to wall by transpeptidation
Cell wall inhibition
Steps in the final stage of bacterial peptidoglycan synthesis have been extensively exploited as drug targets through the development of B-lactams and glycopeptides
In contrast, only some of the many biosynthetic steps in stages one and two are the targets of antibiotics in current clinical use (D-cycloserine, fosfomycin, bacitracin)
Cell wall inhibition- beta lactams
Penicillin V, penicillin G
Bactericidal action against growing and dividing bacteria
Inhibit the final cross linking stage of the peptidoglycan production, binding to and inactivating transpeptidases
Autolysin
Penicillin treated bacteria grown in an isotonic media survive, cell lysis caused by inactivation of inhibitors of autolysins
Autolysin: an enzyme that hydrolyses and breaks down the components of a biological cell, present in all bacteria that have a peptidoglycan
Hydrolyses the B 1,4 bond between N-acetylmuramic acid and N-acetylglucosamine molecules
Indications of penicillin V
Oral infections, tonsillitis, otitis media, pneumococcal infection prophylaxis
Dose e.g. 500mg every 6 hours (1g/6h in severe infection)
Indications of ampicillin (broad spectrum)
UTI, otitis media, sinusitis, oral infections, bronchitis, influenza infections, invasive salmonellosis, listeria meningitis
Dose e.g. 0.25-1g every 6 hours
Indications of amoxicillin (broad spectrum)
UTI, otitis media, sinusitis, oral infections, bronchitis, influenza infections, invasive salmonellosis, listeria meningitis, endocarditis prophylaxis and treatment, anthrax, H pylori eradication
Dose e.g. 250mg/8 h
Combinations of broad spectrum penicillins
Co-amoxiclav: amoxicillin and clavulanic acid, use against B lactamase producing strains, RTI, genito-urinary and abdominal infections, cellulitis
Co-fluampicil: flucloxacillin and ampicillin, use against B-lactamase producing staphylococci
Anti-pseudomonal penicillins
Piperacillin: infection with Ps aeruginosa, LRI, UTI, intra-abdominal and skin infections, septicaemia
Dose e.g. infusion 2.25g/6-8h
Amoxicillin: severe infections with pseudomonas and proteus spp. and bacteroides fragilis
Dose e.g. 3.2g/ 6-8h
