Cell Wall Synthesis
Inhibitors
By
S.Bohlooli, PhD
Inhibitors of Cell Wall Synthesis






Penicillins
Cephalosporins
Monobactams
Carbapenems
Glycopeptides
Other Cell Wall- or Membrane-Active Agents
Chemical Structure
Chemical Structure
Penicillins



In 1928, Alexander Fleming was researching
vaccines and noticed a culture of staphlococci had
undergone lysis from contamination with a mold
Fleming finally isolated the mold, Penicillium
notatum, and found that the fluid beneath it possessed
antibacterial properties
Basic structure consists of thiazolidine ring connected
to b-lactam ring, to which is attached a side chain
Structure of penicillins and products of their enzymatic hydrolysis.
Chemical structure ,major variants
Chemical structure ,major variants
Cell envelope of a gram-negative bacterium
Biosynthesis of cell wall
peptidoglycan
Mechanism of Action




Interferes with last step of bacterial cell wall
synthesis, causing cell lysis
Bactericidal
Only effective against rapidly growing
organisms that synthesize a peptidoglycan cell
wall
Inactive against mycobacteria, fungi, viruses
Mechanism of Action
way of being bactericide

Penicillin binding proteins


Inhibition of transpeptidase


Enzymes involved in forming cross linkages between
peptidoglycan chains inactivated by penicillin
Hinders last step in formation of cross links needed for cell
wall integrity
Autolysins

Normally degrade cell wall, but penicillin prevents new
synthesis
Antibacterial Spectrum




Natural penicillins
Antistaphylococcal penicillins
Extended spectrum penicillins
Antipseudomonal penicillins
Natural Penicillins

Penicillin G (Benzylpenicillin)



Gram +/- cocci, Gram + bacilli, spirochetes,
anaerobes
Susceptible to inactivation by b-lactamase
Penicillin V



Similar spectrum
More acid stable than Pen G
Higher minimum inhibitory concentration
Bacteria Susceptible to Penicillin

Strep pneumonia


Gonorrhea


Major cause of bacterial pneumonia in all ages
Neisseria gonorrhea and meningitidis
Syphilis

Treponema pallidum
Antistaphylococcal penicillins






Methicillin
Nafcillin
Oxacillin
Dicloxacillin
All are penicillinase-resistant penicillins used
in penicillinase-producing staphylococci
Methicillin-resistant staph aureus
Extended Spectrum Penicillins





Ampicillin
Amoxicillin
Activity against haemophilus influenza,
proteus mirabilis, E. coli, and neisseria species
Resistance due to plasmid mediated
penicillinase
May use clavulanic acid or sulbactam to
extend the antibacterial activity
Antipseudomonas Penicillins






Carbenicillin
Ticarcillin
Piperacillin
Azlocillin
Mezlocillin
Effective against pseudomonas aeroginosa and
other gram negatives
Penicillins and Aminoglycosides


Synergistic
Inactivate each other if placed in same IV fluid
bag because of positively charged
aminoglycosides and negative penicillins
Specific Indications for Penicillin








Narrow-spectrum bactericidal
Most Gm+ cocci and rods and anaerobes
Intravenous: Pen G (potassium or sodium)
Intramuscular: Benzathine or procaine Pen G
Oral: Pen V
Pen V, G well distributed in soft tissues
Bone level is fraction of plasma concentration
Excreted primarily via kidneys
Bacterial Resistance
b-lactamase activity
1.
•
•
Decreased permeability to drug
Altered penicillin binding proteins
2.
3.
•
4.
Hydrolyzes cyclic amide bond of b-lactam ring
Usually acquired by transfer of plasmids
May require greater antibiotic concentrations
Efflux
b-lactamase Inhibitors





Clavulanic acid: product of streptomyces
clavuligerus
Irreversibly binds b-lactamases and inactivates
them
Augmentin: amoxicillin + clavulanic acid
Timentin: ticarcillin + clavulanic acid
Unasyn: ampicillin + sulbactam
Pharmacokinetics

Administration


Absorption




Oral, IV, IM
Amoxicillin most completely absorbed
Pen G absorption impeded by food in stomach
Administered at least 1–2 hours before or after a
meal.
Distribution


All cross placenta
Minimal penetration into bone and CSF
Pharmacokinetics (con’t)

Metabolism


Minimal, except in renal failure
Excretion



Kidney
Adjust dose in renal compromise
Probenecid inhibits penicillin secretion
Adverse Reactions

Hypersensitivity- 1-10% patients treated









Penicilloic acid- hapten for immune reaction
Urticaria to angioedema to anaphylaxis
b-lactam cross reactivity
Diarrhea- disruption of flora- ampicillin
Nephritis- methicillin
Neurotoxicity- intrathecal or seizure disorders
Platelet dysfunction- carbenicillin, ticarcillin
Cation toxicity- watch sodium (congenstive heart failure)
and potassium (cardiac toxicity esp in renal failure pts)
Skin rashes-ampicillin and amoxicillin
Allergic Reactions

Acute (< 30 min)


Accelerated (30 min-48 hrs)


Urticaria, angioedema, bronchoconstriction, GI, shock
Urticaria, pruritis, wheezing, mild laryngeal edema,
local inflammatory reactions
Delayed (> 2 days)


Skin rash
Oral glossitis, flurred tongue, black and brown tongue,
cheilosis, severe stomatitis with loss buccal mucosa
Allergic Reactions



Mild: Diphenhydramine 25-50 mg IV/IM/PO
Severe: Epinephrine 0.03-0.05 mg
Skin tests: benzylpenicilloyl-polylysine
Cephalosporins




Cephalosporium acremonium, first source,
isolated in 1948
b-lactam antibiotics
Related to penicillins structurally and
functionally
More resistant to b-lactamases
Antibacterial Spectrum





First generation
Second generation
Third generation
Fourth generation
Increased generation number, increased gram
negative bacterial susceptibility, increased blactamase resistance, decreased efficacy
against gram +
First Generation




Gram + cocci, gram - bacilli, oral anaerobes
Staphylococcus aureus, Proteus mirabilis, E.
coli, Klebsiella pneumonia
Cefazolin, Cephalothin (parenteral)
Cephalexin, Cefadroxil, Cephradine (oral)
Second Generation






Less active against G+, more GHaemophilus influenzae, Enterobacter
aerogenes, Neisseria
Cefaclor, Cefuroxime axetil (Oral)
Cefamandole, Cefonicid, Cefuroxime,
Cefotetan, Ceforanide (Parenteral)
Cefoxitin- Bacteroides fragilis
Used with aminoglycosides for G - bacilli
Third Generation








More Gm – bacilli, Serratia marcescens
Cefixime (Oral)
Cefotaxime
Ceftizoxime
Ceftazidime
Cefoperazone
Ceftriaxone
Cefpodoxime
Fourth Generation



Similar spectrum to third generation
More resistance to b-lactamases
Cefepime hydrochloride
Cephalosporins Active Against
Methicillin-Resistant Staphylococci



Ceftaroline fosamil
Ceftobiprole medocaril
Binding to penicillin-binding protein 2a
Resistance


Similar to penicillins
Limited cross resistance with penicillin, except
with staph and strep pneumonia
Pharmacokinetics


Administration
Distribution



Distributed well through body fluids
Only third generation well into CSF
Excretion


Renal elimination
Cefoperazone and ceftriaxone excreted through
bile and feces
General Therapeutic Uses

Acute respiratory infection


Gonorrhea and H. influenza


Ceftriaxone
Enterobacter, Serratia, E.Coli, Providencia,
Salmonella


First and second generation
Third generation
Gram negative meningitis and septicemia

Third generation
Adverse Effects

Allergy- 15% cross sensitivity with Pen allergy


Disulfiram-like effect


Cefamandole, cefoperazone when ingested with alcohol
block second step in oxidation and aldehyde accumulation
Bleeding


1-2% without Pen allergy
Cefamandole, cefoperazone- anti-vitamin K effects
Renal, hepatic dysfunction
Carbapenems



Synthetic b-lactam antibiotics
Differ from penicillin in sulfur atom of
thiazolidine ring
Imipenem



Combined with cilastin- broadest spectrum blactam antibiotic available against penicillinaseproducing Gram + and -, anaerobes, and
pseudomonas
Resists b-lactamase hydrolysis
Meropenem, doripenem, ertapenem

Greater activity against gram-negative aerobes
Carbapenems




Intravenous use
Penetrates well into CNS
Excreted by kidneys
Toxic metabolite may cause nephrotoxicity


Administered with cilastin to prevent cleavage and
toxic metabolite formation
Nausea, vomiting, diarrhea, seizures,
eosinophilia, and neutropenia
Monobactams





Narrow spectrum- enterobacteriaceae,
pseudomonas; no gram + or anaerobic activity
Resistant to b-lactamase
Aztreonam IV or IM
Phlebitis, skin rash, abnormal liver function
tests
Little cross reactivity with penicillin
Vancomycin





It binds firmly to the D-Ala-D-Ala terminus and
inhibits transglycosylase.
Narrow-spectrum against methicillin-resistant
staphylococci and pseudomembranous colitis caused
by clostridium difficile
Prophylaxis for subacute bacterial endocarditis in
penicillin allergic patients for high risk surgery
Oral route only for P. colitis
IV for systemic infections
Vancomycin




Minimal resistant bacteria, but not vancomycin
resistant enterococci (VRE)
Renal elimination
Fever, chills, phlebitis at infusion site, rash
with chronic administration, ototoxicity
(cochlear damage above 80 mg/ml),
nephrotoxicity
Slow IV administration- fast causes histamine
release (“red man syndrome”), hypotension
Newer glycopeptide antibiotics

Teicoplanin


Dalbavancin



It can be given intramuscularly
Derived from teicoplanin
Effectrive on methicillin-resistant and vancomycinintermediate S aureus
Telavancin



Derived from vancomycin
active versus gram-positive bacteria
including strains with reduced susceptibility to
vancomycin
Other Cell Wall- or Membrane-Active Agents

Daptomycin




Fosfomycin




Novel cyclic lipopeptide
Similar to that of vancomycin
Active against vancomycin-resistant strains of enterococci
and S aureus
Analog of phosphoenolpyruvate
Active against both gram-positive and gram-negative
Cycloserine
Bacitracin
Mechanism of action of daptomycin
Bacitracin




Bacitracin inhibits cell wall synthesis by interfering
with dephosphorlyation in cycling of the lipid carrier
Effective against Gram positive microorganisms
Topical application due to nephrotoxicity
Often used for traumatic abrasions