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1. MODE OF ACTION OF PENICILLIN ON
BACTERIAL CELL WAAL
BY,
SHUBHAM DUBEY ,
TYBSC (MICROBIOLOGY )

2. • What are Antibiotics?
• Antibiotics: chemical substances produced by
microorganisms that inhibits the growth or kills other
microorganisms
• Antimicrobial agents: chemical substances
from a biological source or produced by chemical
synthesis that kills or inhibits the growth of
microorganisms

3. Introduction of Penicillin
• Penicillin is derived from the Penicillium mold
• •It destroys bacteria by inhibiting the enzymes responsible
for the formation of the cell wall in the bacterial cells
• Penicillin is a group of antibiotics that are commonly used
to treat different types of gram positive and gram negative
bacterial infections.
• In their structure, beta-lactam ring is located due to this
reason these drugs are also called as beta-lactam antibiotics.

4. HISTORY of Penicillin
• The world's first antibiotic, was discovered by British scientist
Alexander Fleming in 1928 on accident.
• Bread mold (Penicillium notatum) growing on petri dish.
• In 1928 Alexander Fleming discovered the compound produced by
the fungus
• The fungus was called Penicillium notatum
• Fleming noted a fungus growing on his bacterial plates had killed off
the surrounding bacteria.
• The naturally occurring
penicillins, penicillin G (benzylpenicillin) and penicillin V (phenoxym
ethylpenicillin), are still used clinically.

5. Penicillin G & V

6. Inhibitors of Cell Wall Synthesis:
The Penicillins
• Penicillins as well as cephalosporins are called beta-
lactam antibiotics and are characterized by three
fundamental structural requirements:
1. the fused beta-lactam structure (shown in the
blue and red rings,
2. a free carboxyl acid group (shown in red
bottom right),
3. one or more substituted amino acid side
chains (shown in black),
• The lactam structure can also be viewed as
the covalent bonding of pieces of two amino acids -
cysteine (blue) and valine (red),
• The beta-lactam nucleus itself is the chief
structural requirement for biological activity,
• metabolic transformation or chemical alteration of
this portion of the molecule causes loss of all
significant antibacterial activity,

7. Mechanism of Actions of Beta lactams
—
All penicillin derivatives produce their
bacteriocidal effects by inhibition of
bacterial cell wall synthesis.
—
Specifically, the cross linking of
peptides on the mucosaccharide
chains is prevented. If cell walls are
improperly made cell walls allow water
to flow into the cell causing it to burst.

8. The cell walls of bacteria are essential for their normal growth and
development.
The peptidoglycan (which provide rigid mechanical stability) is
composed of glycan chains, which are linear strands of two alternating
amino sugars (Nacetylglucosamine and N-acetylmuramic acid) that
are cross-linked by peptide chains. (NAG-NAM).
In gram-positive microorganisms, the cell wall is 50 to 100 molecules
thick, but it is only 1 or 2 molecules thick in gram-negative bacteria
Bacteria Cell Wall Synthesis

9. Bacteria Cell Wall
Synthesis
• The biosynthesis of the peptidoglycan involves about 30 bacterial
enzymes and may be considered in three stages.
1) The first stage is precursor formation in the cytoplasm. The
product, uridine diphosphate (UDP)-acetylmuramyl-
pentapeptide, called a "Park nucleotide“.
2) The last reaction in the synthesis of this compound is the
addition of a dipeptide, Dalanyl D-alanine.
3) The second stage, UDP-acetylmuramyl-pentapeptide and UDP-
acetylglucosamine are linked to form a long polymer.
4) The third and final stage involves the completion of the cross-
link. This is accomplished by a transpeptidation reaction that
occurs outside the cell membrane.
• The transpeptidase itself is membrane bound. The terminal
glycine residue of the pentaglycine bridge is linked to the fourth
residue of the pentapeptide (D-alanine), releasing the fifth
residue (also D-alanine).

10. The PBPs and Binding
of Penicillins
• Related targets of penicillins and cephalosporins
collectively termed penicillin binding proteins
(PBPs)
• PBPs functions are diverse: catalyze the
transpeptidase reaction, maintam shape, forms
septums during division, Inhibit autolytic
enzymes.
• Binding to PBPs results in:
• Inhibition of transpeptidase: transpeptidase
catalyzes the cross-linking of the pentaglycine
bridge with the fourth residue (D-Ala) of
the pentapeptide. The fifth reside (also D-Ala) is
released during this reaction. Spheroblasts are
formed.
• Structural irregularities: binding to PBPs may
result in abnormal elongation, abnormal shape,
cell wall defects.
The transpeptidase reaction in Staphylococcus
aureus that is inhibited by penicillins and cephalosporins.

12. Pharmacokinetics
 Oral Administration of Penicillin G. About one-third of an orally
administered dose of penicillin G is absorbed from the intestinal
tract under favorable conditions.
 Gastric juice at pH 2 rapidly destroys the antibiotic.
The decrease in gastric acid production with aging accounts
for better absorption of penicillin G from the gastrointestinal tract
of older individuals.
 Absorption is rapid, and maximal concentrations in blood are
attained in 30 to 60 minutes. The peak value is approximately 0.5
unit/ml (0.3 mg/ml) after an oral dose of 400,000 units (about 250
mg) in an adult.
 Ingestion of food may interfere with enteric absorption of all
penicillins, perhaps by adsorption of the antibiotic onto food
particles. Thus, oral penicillin G should be administered at least
30 minutes before a meal or 2 hours after. Despite the
convenience of oral administration of

13. Parenteral Administration of Penicillin G
• After intramuscular injection, peak
concentrations in plasma are reached within 15 to
30 minutes. This value declines rapidly, since the
half-life of penicillin G is 30 minutes.
• Repository preparations of penicillin G are
employed. The two such compounds currently
favored are penicillin G procaine (maintained for as
long as 4 to 5 days.) and penicillin G benzathine.
(duration of antimicrobial activity in the plasma is
about 26 day)
• Such agents release penicillin G slowly from the
area in which they are injected and produce
relatively low but persistent concentrations of
antibiotic in the blood.
• Intrathecal administration is inadvisable
particularly with benzylpenicillin as it can cause
convulsions.

14. Distribution of penicillin
• Penicillin G is distributed widely throughout the body, but the concentrations in various
fluids and tissues differ widely. Its apparent volume of distribution is about 0.35 liters/kg.
Approximately 60% of the penicillin G in plasma is reversibly bound to albumin. Significant
amounts appear in liver, bile, kidney, semen, joint fluid, lymph, and intestine.
• While probenecid markedly decreases the tubular secretion of the penicillins, this is not
the only factor responsible for the elevated plasma concentrations of the antibiotic that
follow its administration. Probenecid also produces a significan decrease in the apparent
volume of distribution of the penicillins.
• Cerebrospinal Fluid. Penicillin does not readily enter the CSF when the meninges are
normal. However, when the meninges are acutely inflamed, penicillin penetrates into
the CSF more easily. Although the concentrations attained vary and are unpredictable, they
are usually in the range of 5% of the value in plasma and are therapeutically effective
against susceptible microorganisms.

15. Penicillin Excretion
• Under normal conditions, penicillin G is rapidly
eliminate from the body, mainly by the kidney but in
small part in the bile and by other routes.
Approximately 60% to 90% of an intramuscular dose
of penicillin G in aqueous solution is eliminated in the
urine, largely within the first hour after injection.
• The half-time for elimination is about 30 minutes
in normal adults (upto 10 hours in renal failure) .
Approximately 10% of the drug is eliminated by
glomerular filtration and 90% by tubular secretion.
• Renal clearance approximates the total renal
plasma flow. The maximal tubular secretory capacity
for penicillin in the normal male adult is about 3
million units (1.8 g) per hour.

16. Clearance values are considerably lower in neonates and infants, because of
incomplete development of renal function; as a result, after doses proportionate to
surface area, the persistence of penicillin in the blood is several times as long in
premature infants as in children and adults.
The half-life of the antibiotic in children less than 1 week old is 3 hours; by 14 days
of age it is 1.4 hours. After renal function is fully established in young children, the
rate of renal excretion of penicillin G is considerably more rapid than in adults.
Penicillin Excretion​ cont....

17. Unitage of Penicillin
• The international unit of penicillin is the specific
penicillin activity contained in 0.6 mg of the
crystalline sodium salt of penicillin G. One milligram
of pure penicillin G sodium thus equals 1667 units;
1.0 mg of pure penicillin G potassium represents
1595 units. The dosage and the antibacterial potency
of the semisynthetic penicillins are expressed in
terms of weight.
• The minimum inhibitory concentration(MIC) of
any penicillin is usually given in ug/ml( microgram
per milliliter).
• Most penicillins ae dispensed as the sodium or
potassium salt of the free acid.

18. Other Inhibitors of Cell Wall Synthesis:
Fosfomycins
• Spectrum of Action
1. Fosfomycin: Acts to inhibit cell wall synthesis at a
stage earlier than the penicillins or cephalosporins.
FDA approved 1996.
2. It is a broad spectrum agent
• Mode of Action:
1. Inhibits the first step of the peptidoglycan synthesis
2. process (Actual step of inhibition is not completely
understood)

19. Therapeutic Uses
• Pneumococcal Infections
(Streptococcus pneumoniae)
• Streptococcal Infections ( pharyngitis, scarlet fever)
• Staphylococcal Infections (food poisoning, toxic
shock syndrome)
• Meningococcal Infections ( Neisseria meningitidis)
• Syphilis Infections
• Actinomycosis Infections (persistent fever. Pain.)
• Diphtheria
• Rat-Bite Fever
• Lyme Disease
• Erysipeloid
• Surgical Procedures in Patients with Valvular Heart
Disease
This Photo by Unknown author is licensed under CC BY-SA.

20. Mechanisms of Bacterial Resistance to Penicillins
Resistance to penicillins and other beta lactams is due to one of four general mechanisms:
1. Inactivation of the antibiotic by beta lactamase
2. Modification of target PBPs
3. Imparied penetration of drug to target PBPs
4. The presence of an efflux pump.
There are more than 300 different types of this enzyme. The process is genetically controlled
commonly with plasmids.
beta-lactamase production is particularly important in Staphylococci but other organisms such as
Neisseria gonorrhoeae and Hemophilus species also produce these enzymes where as beta-hemolytic
Streptococci do not.
• In developed countries at least 80% of Staphylococci now produce beta-lactamase.

21. • Mass production of the new drug for use in
World War II
• Penicillin saved many lives during the war that may
have been lost due to infected wounds
• Penicillin was also said to treat diphtheria, gangrene,
pneumonia, syphilis and tuberculosis
• Penicillin- first antibiotic to be used clinically
• Fleming received the Nobel Prize in 1945