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BY:
PROF: DR: MANZOOR AHMED UNAR
2018

PENICILLINS

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 Antimicrobial:
Chemical that “kills” or “inhibits the growth”
of microorganisms.

Antibiotic:
Chemical produced by a microorganism that
“kills” or “inhibits the growth” of
another microorganism.

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 Mechanisms of Antimicrobials

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 Classification

Β - LACTAM ANTIBIOTICS OTHER ANTIBIOTCS

Penicillins Vancomycin

Bacitracin
Cephalosporins

Carbapenems Daptomycin

Monobactams Cycloserine

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 Β - LACTAM ANTIBIOTIC
PENICILLIN
 β-Lactam Antibiotics are the products of
two types fungi, Penicillium & Cephalosporium
 Penicillins are β- Lactam drugs.
because of unique four – member ring.

 A Thiazolidine ring is attached to a β- Lactam ring,

 Also carries a secondary amino group (R-NH).
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 Β - LACTAM ANTIBIOTIC
PENICILLIN

Substituent ( R ) can be attached to the amino group

of the 6-amino penicillanic acid nucleus essential for
biologic activity.

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 PENICILLIN

Side chain effects:

• Antimicrobial
spectrum

• Stability to
stomach acid

• Susceptibility to
β-lactamase,
( or Penicillinase

formed by
bacteria)
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 PENICILLIN
Role of Penicillinase

O
S
CH3
R C NH CH CH C
CH3
O C N CH COOH

Site of Penicillinase action

Breakage of the  lactam ring.

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 Β - LACTAM ANTIBIOTIC
PENICILLIN
 β- Lactam ring can be enzymatically cleaved by
“ Bacterial-β-Lactamase (Pencillinase)”
 Resulting product “Penicilloic acid”, lacks
antibacterial activity.

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 Β – LACTAM ANTIBIOTIC
PENICILLIN

Penicillin-G Penicillin-V
Methicillin Nafcillin
Oxacillin Cloxacillin
Dicloxacillin Carbencillin
Ampicillin Amoxicillin
Ticarcillin Pipracillin

Azlocillin Mezlocillin

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 BACTERIAL CELL WALL

Cell wall is rigid outer layer (not found in animal cells),

It completely surrounds the cytoplasmic membrane,
Preventing cell lysis from high osmotic pressure,
Maintain the shape of the cell.

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 BACTERIAL CELL WALL

 Cell wall is composed of a

complex cross linked polymer of
Polysaccharides & Polypeptides,
“Peptidoglycan”.

 Polysaccharides contains
alternating amino sugars,
N-Acetyl Glucosamine (NAG)
&
N-Acetyl Muramic acid (NAM).

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 BACTERIAL CELL WALL

 Five amino acid peptide is linked to N-Acetyl-Muramic

acid (NAM).
 This peptide terminates
in D-alanyl-D-alanine.
 Penicillin-Binding Protein
(PBP, an enzyme)
removes the terminal
alanine & form a cross
link with a nearby
peptide & gives
cell wall rigidity.
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 Β- LACTAM ANTIBIOTIC
Mechanism Of Penicillin
Penicillin only effective against rapidly growing
organism that synthesize a peptidoglycan cell wall.
All β-Lactam antibiotics, inhibits bacterial growth by

interfering with the transpeptidation (cross-linkage)

reaction of bacterial cell wall synthesis.

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 Β - LACTAM ANTIBIOTIC
Mechanism Of Penicillin
 Β-Lactam antibiotics, structural analogs of the natural
D-Ala-D-Ala substrate, covalently bind to active site
of PBP, inhibits Transpeptidation reaction.
 Halting Peptidoglycan synthesis, and the cell dies.

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 Β - LACTAM ANTIBIOTIC
Mechanism Of Penicillin
1. Inactivation of Penicillin Binding Proteins (PBP):
PBP present on the bacterial cell membrane,
involved in synthesis of cell wall.

2. Inhibition of Transpeptidase:
Penicillin inhibit the transpeptidase, thus hindering
the formation of cross links, which is essential for
cell wall integrity.
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 Β - LACTAM ANTIBIOTIC
Mechanism Of Penicillin

3. Production of Autolysins:
Many bacteria (Gram positive cocci) produce
degradative enzymes (autolysins).
That participate in normal remodeling of bacterial
cell wall.

In the presence of Penicillin (absence of cell wall

synthesis) degradation action of autolysins proceeds.

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 Β - LACTAM ANTIBIOTIC
Resistance Mechanisms of Penicillin

 Resistance to β-Lactams is due to:

Inactivation by β - Lactamase,

Impaired penetration of drug

to target PBP,

Modification of target PBP,

Presence of an efflux pump.

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 Antibacterial Spectrum of Penicillin
Three classes of Penicillin,
based upon their ability

Gram positive
to kill various types of bacteria.

Natural Penicillin.

Penicillin Resistant to
Staphylococcal
Beta-Lactamase.

Extended-Spectrum

Gram negative
Penicillin.

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 Natural Penicillin
Penicillin G, Penicillin V, Procaine, Benzathine

 Obtained from fermentation of mold penicillium.

 They are inactivated by many β-Lactamases.

 Effective against Gram-positive organisms,

Gram negative cocci, and
non- β-lactamase producing anaerobes.

 They have little activity against Gram-negative rods .

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 Penicillin Resistant to Staphylococcal Beta-Lactamase
( Anti-staphylococcal )
Oxacillin, Cloxacillin, Dicloxacillin, Methicillin, Nafcillin ,

 More narrow spectrum of activity than the natural

penicillin.
 Antimicrobial efficacy is directly against the
penicillinase producing strains of staphylococci &
streptococci.
 They are inactive against enterococci,
anaerobic bacteria & Gram negative cocci & rods
 All are acid-stable, used 1 hour before meal.

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 Extend – Spectrum Penicillin
Aminopenicillin: Ampicillin, Amoxicillin, Bacampicillin

 Similar to penicillin G , but more active against

Gram-negative bacteria (E. coli & H. influenzae).

 Aminopenicillin are acid-resistant, administered orally.

 They are inactivated by many β-Lactamases.

 Amoxicillin & Ampicillin are used primarily to treat the

mild infections such as otitis media, sinusitis, bronchitis,
urinary tract infections & bacterial diarrhea.

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 Extend – Spectrum Penicillin
( Anti- Pseudomonas)

 Carboxy-penicillin: Carbenicillin, Ticarcillin

 Ureido-penicillin: Piperacillin, Azlocillin, Mezlocillin

 Similar spectrum of activity as the Aminopenicillin but,

with additional activity against Pseudomonas.
 Ureido-penicillin are also active against selected
Gram-negative bacilli (Klebsiella pneumoniae).

 They are susceptible to inactivation by beta-lactamase.

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 Β - LACTAMASE INHIBITORS
Sulbactam, Clavulanic, Tazobactam

Ampicillin with Sulbactam

Ticarcillin with Clavulanic

Pipracillin with Tazobactam

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 Pharmacokinetics of Penicillin

Administration:

 Penicillin-V & Amoxicillin combined with

Clavulanic acid are only available as oral preparation.

 Ampicillin, Methicillin, Ticarcillin, Carbencillin,

Mezlocillin, Azlocillin, Pipracillin used I / V, I / M

 Procaine Penicillin G & Benzathine Penicillin G

used I / M, serve as depot forms & absorbed slowly
into the circulation over a long period.

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 Pharmacokinetics of Penicillin

Absorption:
 Most of the Penicillin are incompletely absorbed
(orally) & reach the intestine in sufficient amount,
affect the composition of the intestinal flora.
 Absorption of Penicillin G & Penicillinase - resistant
Penicillin is decreased by food.
 If gastric emptying time is reduced, drugs are
destroyed in the acidic environment.
Metabolism: is insufficient.

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 Pharmacokinetics of Penicillin

Distribution: Through out the body is good.

 All penicillin cross the placental barrier,

non is teratogenic.
 Penetration into bone or cerebrospinal fluid is
insufficient, unless these sites are inflamed.

Excretion: The primary route of excretion is through

tubular secretion and glomerular filtration.

( Probenecid inhibit the secretion of Penicillin )

 Nafcillin is primarily eliminated through biliary route.

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 Side Effects of Penicillin
 Allergic or hypersensitivity reactions: Skin rash, Itching,
difficulty in breathing, anaphylactic shock.
 Allergic to Penicillin also have allergy to Cephalosporin.
 Eosiniphilia, Hemolytic anemia.
 Diarrhea, Vomiting, Nephritis, Neurotoxicity,
 Vaginal itching & discharge,
 White patches in the mouth or on the tongue.
 Nafcillin associated with neutropenia,
 Oxacillin can cause hepatitis,
 Methicillin causes Interstitial nephritis.

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 Microbial
Sources of
Antibiotics

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 PENICILLINS

Other most common side Rare side effects

effects
• Severe abdominal cramps,
White patches in the mouth or • Bloody diarrhea.
on the tongue. • Fever,
• Increased thirst,
Diarrhea, Vomiting, • Severe nausea, vomiting,
• Tiredness or Weakness,
Headache, • Weight loss,
• Seizures.
Vaginal itching and discharge,

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 Antimicrobial agent:
Chemical that “kills” or “inhibits the growth”
of microorganisms

Antibiotic:
Chemical produced by a microorganism that
“kills” or “inhibits the growth” of
another microorganism

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 Micro-Organisms

Bacteria have their own enzymes for

Cell wall formation
Protein synthesis
DNA replication
RNA synthesis
Synthesis of essential metabolites

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 Fleming & Penicillin

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 Rigid Bacterial Cell wall

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 Peptidoglycan synthesis
Cytoplasm Cell Membrane Cell wall

undecaprenol

sugar

amino
acid

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 Beta lactams
Cell wall

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Penicillin
PUMHSW
binding protein 45
 Cross-linking of peptidoglycan

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STRUCTURE OF PENICILLIN

O
S
CH3
C NH CH CH C
CH3
O C N CH COOH

Site of penicillinase action.

Breakage of the  lactam ring.

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STRUCTURE OF PENICILLIN

O
S
CH3
C NH CH CH C
CH3
O C N CH COOH

Site of penicillinase action.

Breakage of the  lactam ring.

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 Microbial
Sources of
Antibiotics

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 Gram positive
lipid bilayer peptidoglycan

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
Mycobacteria lam mycolate

 acyl lipid

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 Gram negative lipid + LPS


 porin

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