Inhibitors of cell wall
synthesis
1
Frank Ssengooba- 2023
Inhibitors of cell wall synthesis
β-lactams: all have the β-lactam ring, differ by substitutions
on the structure
Differences confer; spectrum, stability in stomach,
susceptibility to degradative enzymes (β lactamases)
Include;
Penicillins
Carbapenems,
Cephalosporins,
Monobactams
Others:
Bacitracin,
Vancomycin,
Fosfomycin
BACTERIAL CELL WALL
BACTERIAL CELL WALL SYNTHESIS
1. Glycosidic bond breakage by
bacterial autolysins
and peptide cross-bridge breakage
2. Peptidoglycan monomer synthesis in
cytosol and transfer across cytoplasmic
membrane
3. Linkage of new peptidoglycan
monomers into chain by
transglycosylases
4. Cross-linkage of peptides between
peptidoglycan layers to make them
strong
PENICILLINS
Mechanism of action (MoA)
Bind to penicillin binding proteins (PBPs) – enzymes (transpeptidases,
carboxypeptidases, transglycosylases) necessary for synthesis and
maintenance of cell wall
Inhibition of transpeptidase – prevents transpeptidase-catalysed cross-
linkage of peptidoglycan chains
Activate autolysins – self degradative enzymes responsible for
remodeling of cell wall
Mechanisms of resistance (MoR)
1. β-Lactamase (penicillinase) activity: the enzyme hydrolyses the β-
lactam ring, resulting in loss of bactericidal effect
2. Decreased permeability to penicillin:
a. the presence of an efflux pump which reduces intracellular
concentration of the drug
b. absence of porins (protein channels) which impairs penicillin
entry
3. Alteration of PBPs: reduced affinity of the modified PBP for penicillin,
hence no binding
ANTIBACTERIAL SPECTRUM AND INDICATIONS
Narrow spectrum, penicillinase
sensitive
Gram+ organisms, anaerobes
Antistaphylococcal penicillins,
Penicillin G (benzylpenicillin),
Penicillin V penicillinase –resistant
Isoxazol group: Oxacillin,
(phenoxymethylpenicillin)
Procaine and Benzathine cloxacillin, dicloxacillin,
benzylpenicillin Nafcillin, methicillin (no longer
used)
Indications: I: Used for infections due to
Streptococcal tonsillitis penicillinase–producing
Pharyngitis staphylococci
Pneumococcal pneumonia
Meningitis,
Meningococcal infection
Syphilis
Gas gangrene
Endocarditis etc.
ANTIBACTERIAL SPECTRUM AND INDICATIONS
Extended spectrum, penicillinase
sensitive Antipseudomonal
Gram+, gram- bacilli penicillins
Aminopenicillins
Ampicillin, amoxycillin • Piperacillin, ticarcillin,
Amoxycillin + clavulanic acid (Co- carbenicillin
•+ tazobactam or clavulanic
amoxiclav): acid
Ampicillin + sulbactam
protect amoxycillin/ampicillin from •P.aeruginosa, E. coli, P. mirabilis,
hydrolysis by penicillinase H. influenzae
I: for respiratory tract infections sinusitis,
bronchitis, STIs, prophylaxis for
abnormal heart valve patient when
undergoing oral surgical procedures •Indications:
•
PENICILLINS: PHARMACOKINETICS
Administration (A):
Penicillin V, co-amoxiclav, flucloxacillin, : acid stable, oral administration
mainly
Penicillin G: orally, high dose; intravenously (IV)
Piperacillin, piperacillin + tazobactam, nafcillin, ticarcillin: parenteral- IV and
intramuscularly (IM)
Procaine- and benzathine benzylpenicillin: strictly IM. IV injection causes
serious life-threatening syndrome that includes cardio-respiratory failure!
Amoxicillin, ampicillin, oxacillin, cloxacillin, dicloxacillin: oral and parenteral
Absorption (Abs): Incomplete, affected by food, hence taken on an empty
stomach 1-2 hours before or after a meal.
Amoxicillin is completely absorbed and is not affected by food.
Procaine BP- slow release, 24hrs; Benzathine BP- several weeks
Distribution (D): Well distributed except in bone, CSF (except in inflammation)
and prostates.
Metabolism (M): insignificant (up to 20%)
Excretion (E): Renally, tubular secretion and glomerular filtration.
PENICILLINS: PHARMACOKINETICS (PKS)
Adverse effects (AEs): hypersensitivity reaction- rash,
angioedema, bronchospasm, anaphylaxis;
nephritis, neurotoxicity, haematologic disorders, cation
toxicities; disturbance of normal flora- diarrhoea, antibiotic-
associated pseudomembranous colitis (AAPMC)
Drug interactions (DIs):
Reduces the efficacy of oral contraceptives, additional
contraception should be taken
Probenecid increases serum levels of penicillin
Allopurinol increases the risk of skin rash
Risk of toxicity increased by potassium-sparring diuretics
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CEPHALOSPORINS o =oral p=parenteral
Structurally and functionally related to penicillins, have same
Mechanism of action; Mechanism of resistance: susceptible to
extended spectrum β-lactamases
NB:Cephalosporins are ineffective against enterococci, L.
monocytogenes, C. Difficile, MRSA
Divided into four generations due to different antimicrobial spectrum
1st generation: Pen G substitutes, effective against gram+ organisms and
penicillinase-producing staphylococci
Also proteus spp, E. coli, Klebsiella pneumoniae [PEcK]
Cefazolinp,cefalotinp,cefadroxilº, cefalexinº, cephradineº. Cefazolin is
widely used for surgical prophylaxis.
2nd generation: 1st generation spectrum + community-acquired gram-
organisms and H. influenzae [HENPEcK]
Cefuroximeº,p, cefoxitinp, cefaclorº
3rd generation: extended spectrum against gram- bacilli
Ceftriaxonep, ceftazidinep: used for bacterial infections including
meningitis
Ceftazidine is also antipseudomonal
Cefepimep, resistant to β-lactamases
4th generation: broad spectrum, gram+, gram- organisms,
antipseudomonal
CEPHALOSPORINS
PKs: Well distributed. 3rd gen enter CSF readily. Renal excretion,
ceftriaxone biliary excretion.
Adverse effects: hypersensitivity reactions
Cross-sensitivity with penicillin (hence contraindicated)
Drug interactions
Oral contraceptives: reduced efficacy
Alcohol: disulfiram effect
Probenecid: prolonged t½ of cephalosporins
Aspirin, NSAIDs, antiplatelets: increased risk of bleeding
Anticoagulants, warfarin: potentiates anticoagulant effect due to
altered Vitamin K metabolism
CARBAPENEMS
Synthetic β -lactams that differ with penicillin by
their thiazolidine ring
Imipenem, meropenem: administered IV, imipenem
metabolised by renal dehydropeptidase
Broad spectrum
Imipenem + cilastin: protected from renal
metabolism
Adverse effects: hypersensitivity, nausea,
vomiting, diarrhea
MONOBACTAMS
Aztreonam
β-lactam ring not fused to another ring
Narrow spectrum: aerobic gram- bacilli, including P.
aeruginosa, Enterobacteriaceae
No activity against gram+ bacteria and anaerobes
Administered parenterally – IV or IM; t½ 1-2hrs, prolonged in
renal failure
Resistant to β -lactamases
Adverse effects: phlebitis, skin rash, abnormal LFT
Safe alternative for penicillin or cephalosporins
VANCOMYCIN
A tricyclic glycopeptide, water soluble
MoA: Inhibits synthesis of bacterial cell wall phospholipids and
peptidoglycan polymerization, weakens cell wall and damages
underlying membrane.
MoR: alteration of the binding site of vancomycin (terminal D-Ala
replaced by D-lactate); changes in permeability to vancomycin
Spectrum and indications
gram+ organisms, β-lactam resistant microbes—MRSA, MRSE,
penicillin-resistant enterococci,
alternative prophylaxis in penicillin-allergic patients with prosthetic
devices undergoing surgical procedures
alternative treatment for life-threatening AAPMC due to C. difficile
VANCOMYCIN
Pharmacokinetics
Poor oral absorption, hence parenterally, slow IV.
Orally taken for AAPMC only! Enters meninges in inflammation.
Renally excreted, unchanged, by glomerular filtration.
T½ = 4 -11hrs, prolonged to 6 -10 days in renal impairment
AEs: serious infusion reactions - fever, chills, flushing ,
palpitations, hypotension, rash with pruritis of face, neck, upper
body (red-man syndrome) [managed by slow IV infusion with well
diluted drug or pre-treat with antihistamine or steroid]
Pain and phlebitis at injection site
Risk of ototoxicity and nephrotoxicity in the renally impaired, the
elderly, high doses, prolonged therapy
DI: aminoglycosides, amphotericin B – risk of ototoxicity is
increased 15
BACITRACIN FOSFOMYCIN
Cyclic peptide derived from
Bacillus subtilis A phosphonate
MoA: inhibits cell wall MoA: inhibits one of the first steps
peptidoglycan synthesis of cell wall synthesis
Spectrum and indications Spectrum and indications
gram + cocci (staphylococci and gram+, gram- organisms;
streptococci) Used as a single 3g dose for
Used for topical treatment of minor uncomplicated UTI in females;
skin and ocular infections prophylaxis in surgical procedures
Pharmacokinetics Pharmacokinetics
Poorly absorbed. Highly oral and parenteral admin; t½ =
nephrotoxic hence is used 4hrs; renal excretion
topically only. Absorption delayed by food
DIs: Metoclopramide- be avoided
