Cell Wall Inhibitors

Penicillins

Lec. 2

Assistant. Prof. Dr. Inssaf IH. Al-Shemmary

 Cell Wall Inhibitors
Some antimicrobial drugs selectively interfere with synthesis of the
bacterial cell wall. The cell wall is composed of a polymer called
peptidoglycan that consists of glycan units joined to each other by
peptide cross-links. To be maximally effective, inhibitors of cell wall
synthesis require actively proliferating microorganisms; they have
little or no effect on bacteria that are not growing and dividing.
1. Penicillins
The penicillins share features of chemistry, mechanism of
action, pharmacology, and immunologic characteristics
with cephalosporins, monobactams, carbapenems, and β-
lactamase inhibitors, all of these antibiotics are called β-lactam
antibiotics due to contain β-lactam ring in their chemical structure.
Chemical Structure of β-lactam antibiotics
Mechanism of Action
The penicillins interfere with the last step of bacterial cell wall
synthesis (transpeptidation or cross-linkage) through PBPs
(penicillin binding protein) and this proteins interfere with the
bacterial cell wall synthesis thus inhibits transpeptidation
resulting in cell lysis, either through osmotic pressure or
activation of autolysins (degradative enzymes that participate
in the bacterial cell wall). Thus penicillins are bactericidal.
Penicillins are only effective against rapidly growing organisms
that synthesize a peptidoglycan cell wall.
Antibacterial Spectrum
In general, gram + ve microorganisms have cell walls that are
easily to cross by penicillins in the susceptible bacteria to these
drugs. Gram - ve bacteria have proteins inserted in the
lipopolysaccharide layer that act as water-filled channels (called
porins) to permit transmembrane entry. The antibacterial effects
of all β-lactam antibiotics are synergistic with the
aminoglycosides.

Classification of Penicillins

1. Natural penicillins
A. Penicillin G (benzyl penicillin). Penicillin G is susceptible to
inactivation by β-lactamases (penicillinases). It is used in therapy
for infections caused by:
• Gram + ve cocci, e.g: Streptococcus.
• Gram +ve bacilli,e.g: Bacillus anthracis
• Gram – ve cocci, e.g: Neisseria.
• Anaerobic organisms, e.g: Clostridium.
B. Penicillin V has a spectrum similar to that of penicillin G. Penicillin
V is more acid-stable than penicillin G, It is often employed orally in
the treatment of infections.

2. Antistaphylococcal penicillins: Methicillin, nafcillin are

penicillinase-resistant penicillins. Because of its toxicity, methicillin is
not used clinically.Methicillin-resistant Staphylococcus aureus (MRSA)
refers to any strain of Staphylococcus aureus that has a multiple drug
resistance to beta- lactam antibiotics. MRSA is usually susceptible to
vancomycin.
3. Extended-spectrum penicillins: Ampicillin and amoxicillin
have an antibacterial spectrum similar to that of penicillin G but
are more effective against gram-negative bacilli. These agents
are also widely used in the treatment of respiratory infections.

4. Antipseudomonal penicillins: Carbenicillin, ticarcillin,

piperacillin are called antipseudomonal penicillins because of
their activity against Pseudomonas and they are effective
against many gram-negative bacilli.
Resistance
A. Natural resistance to the penicillins occurs in organisms that
either lack a peptidoglycan cell wall e.g. mycoplasma or that are
impermeable to the drugs.
B. Acquired resistance to the penicillins by plasmid transfer has
become a significant clinical problem, this due to lactamase activity,
Decreased permeability to the drug, altered PBPs.
Pharmacokinetics
1. Administration: The route of administration of a β-lactam
antibiotic is determined by the stability of the drug to gastric acid and
by the severity of the infection. These drugs are effective by the oral,
IV, or IM routes.
2. Absorption: Most of the penicillins are incompletely absorbed
after oral administration. Oral penicillins except for amoxicillin
should not be given at meal times to minimize binding to food
proteins and acid inactivation.
3. Distribution: The β-lactam antibiotics distribute well throughout
the body, bone, CSF. All the penicillins cross the placental barrier,
but not to be teratogenic.
4. Excretion: The primary route of excretion is tubular secretory
system of the kidney as well as by glomerular filtration. Probenecid
inhibits the secretion of penicillins and, thus can increase blood
levels.
Adverse Effects
1. Hypersensitivity: This is the most important adverse effect,
due to its metabolite (penicilloic acid) which reacts with proteins
and serves as a hapten to cause an immune reaction. This reaction
ranging from rash (the most common rash seen with ampicillin
hypersensitivity) to angioedema (marked swelling of the lips,
tongue, and periorbital area).
2. Diarrhea: It occurs to a greater extent with those agents that are
incompletely absorbed and have an extended with antibacterial
spectrum. Diarrhea appeare to be less frequent with amoxicillin
than ampicillin as with some other antibiotics.
3. Nephritis: All penicillins, but particularly methicillin, have
the potential to cause acute interstitial nephritis.
4. Neurotoxicity: The penicillins are irritating to neuronal
tissue, and they can provoke seizures if injected intrathecally
or very high blood levels are reached. Epileptic patients are
particularly at risk.
5. Hematologic toxicities: Decreased coagulation may be
observed with the antipseudomonal penicillins (carbenicillin
and ticarcillin). eosinophilia.