Cell wall synthesis inhibitors
Dr. Mohammed Al-Khawlani
Assist. Professor of pharmacology and Toxicology
Inhibitors of cell wall synthesis
 Inhibitors of cell wall synthesis:
Agents affecting
the cell wall
b-lactam antibiotics
Non B-lactam
Other antibiotics
Bacitracin
Vancomycin
Daptomycin
Penicillins
Amoxicillin
Ampicillin
Dicloxacillin
Indanyl carbenicillin
Methicillin
Nafcillin
Oxacillin
Penicillin G
Penicillin V
Piperacillin
Ticarcillin
Cephalosporins
Carbapenems
Ertapenem
Imipenem/cilastatin*
Meropenem
1st generation
Cefadroxil
Cefazolin
Cephalexin
2nd generation
Cefaclor
Cefprozil
Cefuroxime
Cefoxitin
Monobactams
Aztreonam
3rd generation
Cefdinir
Cefixime
Cefotaxime
Ceftazidime
Ceftibuten
Ceftizoxime
Ceftriaxone
4th generation
Cefepime
(according to Lippincott´s Pharmacology, 2009)
Inhibitors of cell wall synthesis
1 -B-Lactam Antibiotics:
AS: Penicillins, Cephalosporin, Carbapenem and Monobactam.
 They have the following common characteristics:
a) Contain B-Lactam ring which is essential for anti-bacterial activity.
b) Bactericidal.
c) They bind to specific Penicillin-Binding-Protein (PBP):
 ↓ Transpeptidase enzyme responsible for
cross-linking of peptidoglycans, a final step
in cell wall synthesis → ↓ Cell Wall
Synthesis.
 Activate Autolytic enzymes (Autolysins)
→ Lysis of cell wall
 Bacteria imbibe water due to its interior
high osmotic pressure → Rupture and death
of the bacteria.
d) Selectivity: Human cells do not contain
peptidoglycan cell wall.
B-Lactam Antibiotics
e) Resistance:
- Natural absence of peptidoglycan cell wall e.g. Mycoplasma, Mycobacteria, Fungi, and
Viruses.
- Production of B-lactamase (penicillinases) enzymes. e.g. S. aureus.
- Alteration in the PBP; e.g. MRSA, Pneumococci and enterococci.
- Decreased permeability to antibiotics (eg, Pseudomonas due to loss porin)
f) They do not pass BBB except in cases of inflammation, no hepatic metabolism
B-Lactam Antibiotics
1. Penicillins:
 Derivatives of 6-Aminopenicillanic acid.
 They contain B-lactam ring which is essential for the anti-bacterial activity.
 Obtained:
- Naturally from penicillium molds: penicillin G and penicillin V
- Semi-synthetically: Amoxicillin and Ampicillin
 Most widely effective and safer.
 Increased resistance → limited their use.
 Bactericidal and work in a time-dependent killing.
 They have little or no effect on bacteria that are not
growing and dividing. Only effective against rapidly
growing organisms that synthesize a peptidoglycan
cell wall.
 Classification:
1- Natural penicillins.as: penicillin G and penicillin V
2- Antistaphylococcal penicillins as: Methicillin
3- Aminopenicillins: Amoxicillin and Ampicillin
4- Antipseudomonal penicillins. Piperacillin & Carbenicillin
B-Lactam Antibiotics
A. Natural Penicillin:
1. Short acting natural Penicillin: as Benzyl Penicillin (Penicillin G):
 Rapid onset, short of action, reaches high plasma concentration, The strongest effect.
 The disadvantage:
1)
2)
3)
4)
Acid-sensitive: Not effect orally (given by IV injection).
B-Lactamase (penicillinase)-sensitive: as Staph. aureus.
Short acting due to rapid excretion in urine (4-6 h).
Narrow spectrum:
Effective in:
- Gm + ve cocci: streptococci , non pencillinase producing staphylococci, Pneumococci,
and enterococci (Bacterial endocarditis).
- Gm + ve bacilli: Clostridium. Perfringens (Gas gangrene), C. diphtheria (Diphtheria)
and anthracis (Anthrax).
- Gm- ve cocci: Gonococci (Gonorrheal) and meningococci (meningitis)
- Some organisms (syphilis, actinomycosis).
Inactive against B lactamase producing staphylococci & all Gm-ve bacilli (Salmonella,
Shigella, H. influenza, Helicobacter pylori & E. coli).
Dose: 4-24 million u/day divided every 4-6 h in serious infections: meningitis, gas gangrene, syphilis (DOC)
- Diphtheria, anthraxs and acute & subacute bacterial endocarditis
Penicillin
2. long-Acting natural Penicillin :

a) Acid-sensitive. b) B-Lactamase-sensitive. c) Narrow spectrum .
1) Procaine Penicillin.
-
-
Combination of penicillin G + procaine that have longer duration (12-24 h) and less painful
Moderate plasma concentration.
Used in moderate cases: syphilis , gonorrhea. And As Prophylaxis against subacute endocarditis in patients
with valve disease or prosthetic valves before dental procedures.
Dose: 600'000 U I.M /12-24 h.
2) Benzathine Penicillin (Retarpin)® :
- Slow onset but has longest duration of action among penicillin
-
Used mainly in rheumatic fever (as prophylaxis) and in treatment of
syphilis.
Dose: 1.2 -2.4 million U I.M/ 1-4 Weeks.
3. Acid-Resistant of natural Penicillin:
1) B-Lactamase-sensitive. 2) Narrow spectrum. 3) Short duration of action.
As: Phenoxymethyl Penicillin (Penicillin V):
- Weakest effect against streptococcal , given Orally
-
Used only in minor infections as; streptococcal pharyngitis, (Amoxicillin
is often used instead).
Used as prophylaxis in rheumatic fever (250 mg PO bid).
Dose: 250-500 mg /6-8 hours Orally.
Penicillins
B. Penicillinase (B-Lactamase) Resistant Penicillins (Anti-staphylococci penicillins)
Ex. Methicillin (given I.V only), cloxacillin, dicloxacillin, nafcillin and flucloxacillin (oral
or parenteral)
 a) Narrow spectrum, b) B-Lactamase (penicillinase) –resistant, c) acid resistant (except methicillin).
d) Semisynthetic penicillin.
 They are active against staphylococci and streptococci (weaker than penicillin G). but inactive
against enterococci, anaerobic bacteria, and gram-negative cocci and rods.

Used in the treatment of penicillinase producing staphylococci infections: as Abscess, skin and soft
tissues infection.
 The use of these agents is now declining due to increased
incidence of methicillin-resistant S. aureus (MRSA).
 Methicillin, the first antistaphylococcal penicillin, but rarely
used due to its nephrotoxic

Nafcillin (I.V, I.M) and Oxacillin (orally) are considered the
drugs of choice for serious systemic staphylococcal infections
 May combined with ampicillin to increase spectrum of activity.
Ampicillin + cloxacillin (Ampiclox)®
Ampicillin + dicloxacillin (Cloxapen)®
Penicillins
C. Extended-spectrum penicillins (Aminopenicillin): Ampicillin & Amoxicillin
 a) Acid resistant (effective orally).
b) B-Lactamase sensitive
c) wider spectrum ( Gram +ve & -ve organisms including Gram -ve Bacilli e.g. in respiratory tract
(H.infleunza), UT (E.coli), GIT(salmonella typhi ) but not Pseudomonas, Proteus, and Klebsiella.
1) Ampicillin:
 Incompletely absorbed orally especially in the presence of
food, causing
diarrhea and superinfection.
 Ampicillinis more active on shigella and H. influenza.
 Useful in enteritis (bacillary dysentery)
 Ampicillin + gentamicin is used for Listeria monocytogenes (bacterial meningitis) (DOC)
Dose: 250-500 mg/6 h
2) Ampicillin Esters (Pro-Ampicillins =Ampicillin Prodrugs):
 They are better absorbed orally than ampicillin and accordingly cause minimal diarrhea and
superinfection.
 They are de-esterified in the liver and gut mucosa into active ampicillin.
 They include: Bacampicillin- Talampicillin- Pivampicillin.
Penicillins
3) Amoxycillin (250-500 mg/TID):
 Absorption is much better than ampicillin & longer duration and less affected by food than ampicillin
 Amoxicillin is more active against Salmonella and Streptococcal fecalis.
 Use:
- Respiratory tract infections: pharyngitis, tonsillitis, otitis, sinusitis,
bronchitis, and pneumonia
- Typhoid fever and eradication of H.pylori in peptic ulcer.
- Prophylactically by dentists in subacute endocarditis before dental
procedure
- Urinary tract infection (U.T.I.)
NB: Formulation with a β-lactamase inhibitor, such as clavulanic acid
or sulbactam, protects amoxicillin or ampicillin, respectively, from
enzymatic hydrolysis and extends their antimicrobial spectra.
 B lactamase inhibitors: : Clavulonic acid , sulbactam , tazobactam
 They bind with the enzyme → Irreversible inhibition → Suicide substrate.
 They have very weak or no anti-bacterial activity
 They protect penicillins from inactivation by B-lactamases secreted by
some bacteria e.g. Proteus, E. coli, Pseudomonas, Staph aureus & H.
influenza
 May combined with β– lactamase inhibitors to cover B-lactamase producing bacteria.
- Clavulanic acid+ Amoxicillin = Co-Amoxiclav, E-Moxclav & Augmentin®, .
- Sulbactam + Ampicillin = Unasyn®.
Penicillins
D. Anti-Pseudomonal Penicillins: Piperacillin (most potent) & Ticarcillin, Carbenicillin
a) B-lactamase sensitive
b) acid sensitive
c) Broad spectrum against Gram positive (less active) and negative bacteria (more active) including
Pseudomonas aeruginosa infection.
 They are given with aminoglycosides for pseudomonas infections (pneumonias, UTI, burns) but should
not be mixed in the same syringe or bottle.
 These agents are available in parenteral formulations only.
 They are subdivided into:
Carboxypenicillins: Carbenicillin (IV, IM) – Ticarcillin (IV)
Ureidopenicillins: Piperacillin - Azlocillin- Mezlocillin (IV, IM).

May combined with β– lactamase inhibitors to enhance activity.
Ticarcillin + clavulanic acid: (Timentin)® 3.1 g/4-6 h IV.
Piperacillin + Tazobactam (Zosyn)®
4.5 g/4-6 h IV.
Penicillins
 Pharmacokinetics:
A) Absorption:
1) Acid-Sensitive: destroyed by gastric acidity and accordingly not given orally; e.g. benzyl
penicillin -procaine penicillin -benzathine penicillin- methicillin.
2) Acid-Resistant: e.g. Penicillin V- ampicillin- amoxycillin.
3) Absorption of most oral penicillins ( Except amoxicillin) is impaired by food, and the
drugs should be administered at least 1–2 hours before or after a meal.
B) Distribution: Bound to plasma proteins. Pass placental barrier and are safe in pregnancy.
Not penetrate BBB in normal meninges (pass easily in inflamed meninges)
C) Fate: Penicillins are excreted unchanged (active) in urine by tubular secretion mainly
(Except nafcillin by biliary route and has long duration of action)
1) The dose should be adjusted in cases of renal impairment according to kidney functions.
2) Benzyl penicillin is rapidly excreted and has short duration of action.
3) Probenicid reduces the rate of urinary excretion and accordingly prolongs the duration of
action of penicillins.
Penicillins
 Therapeutic uses of Penicillins:
A) Prophylaxis:
1) Rheumatic fever (Streptococcal infections) by benzathine penicillin (1,200.000 units IM/
month for 5 years or until reaching 21 years of age; which is ever longer. Or penicillin V
250 mg twice daily orally. If Allergic to Penicillins: Erythromycin 250 mg PO bid. Or
Sulfadiazine 1 g PO bid.
2) Endocarditis in patients with valve disease or prosthetic valves before dental procedures.
Procaine penicillin (600,000 units IM) 2-3 hours before dental procedures. Or Amoxicillin 3
g PO 1 hour before tooth extraction.
B) Treatment: see before
Penicillins
 Side effects: (Penicillins are among the safest antibiotics)
1) Hypersensitivity (allergic reactions):
- It is manifestsed as rash, urticaria, angioedema, or anaphylactic shock
- The patient should never re-use penicillins.
- There is cross allergy between penicillins and other B-lactam antibiotics as cephalosporin
in about 10% of population , due to similarity in the chemical structure.
2) Diarrhea, pseudomembranous colitis and superinfection especially with ampicillin.
may be caused by monilia (candida), C.difficile and is treated by Nystatin orally, oral
Vancomycin or Metronidazole.
3) Local pain due to IM injection (benzathine penicillin),
4) Seizures and epileptic fits in case of large doses.
5) Platelet dysfunction leading to bleeding (by carbenicillin, ticarcillin, and rarely benzyl
penicillin).
7) Acute interstitial nephritis by methicillin (not used clinically).
 Contraindications:
I. Allergy.
II. Epilepsy