Penicillins are a group of antibiotics that are derived from the Penicillium mold. They work by inhibiting the final step of bacterial cell wall synthesis through binding to penicillin-binding proteins. This prevents cross-linking of peptidoglycan chains, leading to cell lysis. The first penicillin discovered was penicillin G, which is acid labile and used parenterally. Semisynthetic penicillins were later developed with better stability and absorption, including penicillinase-resistant penicillins effective against Staphylococcus. Extended-spectrum penicillins like ampicillin are also active against common gram-negative bacteria.

1. CELL WALL SYNTHESIS
INHIBITORS
A N.VIJAY KUMAR
November 26, 2013

2. Site and Mechanism of action of Antibiotics

3. Penicillium
The name Penicillium comes from Penicillus = brush, and this is based on
the brush-like appearance of the fruiting structures

4. Introduction

The penicillins constitute one of the most important groups of
antibiotics.

Although numerous other antimicrobial agents have been produced
since the first penicillin became available, these still are widely used,
major antibiotics, and new derivatives of the basic penicillin nucleus
still are being produced.

Many of these have unique advantages, such that members of this
group of antibiotics are presently the drugs of choice for a large
number of infectious diseases.

5. History

1928 - Alexander Fleming

Bread mold (Penicillium notatum) growing on petri
dish

1939 - Florey, Chain, and Associates

Began work on isolating and synthesizing large
amounts of Penicillin.

1941 – introduced in antibacterial therapy

6. Structure
the fused beta-lactam structure (shown in the blue and red
rings,
a free carboxyl acid group (shown in red bottom right),
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).

7. thiazolidine ring (A) connected to a b-lactam ring (B), to which is attached a side
chain (R).

8. 
The penicillin 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

9. 
Clinically useful families of beta-lactam
compounds include the

Penicillins

Cephalosporins

Monobactams

Carbapenems

10. Mechanisms of Action

All penicillin derivatives produce their
bactericidal effects by inhibition of bacterial cell
wall synthesis.

Specifically, the cross linking of peptides on the
polysaccharide chain is prevented.

If cell walls are improperly made cell walls allow
water to flow into the cell causing it to burst.

11. Penicillin
Bind (PBP) on the cell wall of susceptible bacteria
Inhibits transpeptidation
Prevents peptidoglycan synthesis
Cell wall deficient forms spheroplasts &
filamentous forms
Autolysis
Cell death (bactericidal action)

12. MOA: Cell Wall production

The cell walls of bacteria are essential for their normal growth and
development.

Peptidoglycan is a heteropolymeric component of the cell wall that
provides rigid mechanical stability by virtue of its highly cross-linked
latticework structure

The peptidoglycan is composed of glycan chains, which are linear
strands of two alternating amino sugars (N-acetylglucosamine and
N-acetylmuramic acid) that are cross-linked by peptide chains.
(NAG-NAM).

13. Mechanisms of Action

Cont…
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 residue (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.

15. Comparison of the structure and composition of gram-positive and
gram-negative cell walls.

16. CLASSIFICATION

NARROW SPECTRUM PENICILLINS
β -lactamase sensitive(NATURAL PENICILLINS)
Acid resistant
- Penicillin V (oral)
Acid labile
- Penicillin-G (benzyl penicillin)
(I.M,IV)
- Procaine penicillin-G(I.M,depot
inj)
- Benzathine penicillin-G(I.M,
depot inj)

17. β -lactamase resistant(ANTISTEPHYLOCOCCAL
PENICILLINS)
Acid resistant
- Cloxacillin
- Dicloxacillin
- flucloxacillin
Acid labile
- Methicillin (I.M,I.V)
- Nafcillin (I.M,I.V)

18. 
EXTENDED SPECTRUM PENICILLINS
Acid resistant
•
Aminopenicillins: Ampicillin, Amoxicillin, Bacampicillin,
Talampicillin
Acid labile ( ANTIPSEUDOMONAL PENICILLINS)
•
•

Carboxypenicillins: Carbenicillin, Ticarcillin
Ureidopenicillins: Piperacillin, Mezlocillin, Azlocillin
BETA LACTAMASE INHIBITORS
•
Sulbactam, Tazobactam, Clavulanic acid

19. Natural penicillins

Listed as antistaphylococcal

Obtained from fermentations of the mold
Penicillium chrysogenum

Penicillin G (benzylpenicillin) and Penicillin V

20. Antimicrobial spectrum: Penicillin G

21. Pharmacokinetics
Oral administration of Penicillin G:
Acid
labile
About
one-third of an orally administered dose of PenG is
absorbed from the intestinal tract under favorable conditions.
Gastric
juice at pH 2 rapidly destroys the antibiotic.
Parenteral Administration of Penicillin G:
From
I.M site absorption is rapid and complete
Peak
plasma levels attained in 30min

22. Pharmacokinetics

Cont…
PenG is distributed widely throughout the body, but the
concentrations in various fluids and tissues differ widely.

Approx. 60% of the PenG in plasma is reversibly bound to albumin.

Significant amounts appear in liver, bile, kidney, semen, joint fluid,
lymph, and intestine

CSF: 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.

Little metabolized because rapid excretion

23. Pharmacokinetics

Cont…
The half-time for elimination is about 30 minutes in
normal adults (upto 10 hours in renal failure) .

Approx. 10% of the drug is eliminated by glomerular
filtration and 90% by tubular secretion .

While probenecid markedly ↓ss 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.

24. Preparations and dose


Benzylpenicillin (sodium and potassium
salts)
Repository preparations:



Insoluble salts, only I.M injection never I.V inj
Procaine penicillin
Benzathine penicillin

25. Unitage of Penicillin

The IU of penicillin is the specific penicillin activity
contained in 0.6 mg of the crystalline sodium salt of
penicillin G.

1mg of pure penicillin G sodium thus equals 1667 units;
1mg of pure penicillin G potassium represents 1595 units.

The dosage and the antibacterial potency of the
semisynthetic penicillins are expressed in terms of weight.

26. Therapeutic Uses















Pneumococcal Infections
 Pneumococcal Meningitis
 Pneumococcal Pneumonia
Streptococcal Infections
 Streptococcal Pharyngitis (including Scarlet Fever)
 Streptococcal Pneumonia, Arthritis, Meningitis, and Endocarditis
Staphylococcal Infections
Meningococcal Infections
Gonococcal Infections
Syphilis, Actinomycosis, Diphtheria, Anthrax
Clostridial Infections
Fusospirochetal Infections
Rat-Bite Fever
Listeria Infections
Lyme Disease
Erysipeloid
Surgical Procedures in Patients with Valvular Heart Disease
Tetanus and gas gangrene
Prophylactic uses:

Rheumatic fever, bacterial endocarditis and agranulocytosis pts

27. Mechanisms of Bacterial
Resistance to Penicillins

Resistance to penicillins and other beta
lactams is due to one of four general
mechanisms:




Inactivation of the antibiotic by beta lactamase
Modification of target PBPs
Impaired penetration of drug to target PBPs
The presence of an efflux pump.

28. Other resistance mechanisms



A reduction in the permeability of the
outer membrane.
Thus there is a decreased ability of the
drug to penetrate to the target site.
The occurrence of modified penicillin
binding sites. This mechanism is
responsible in methicillin resistance in
Pneumococci.

29. Adverse effects

Hypersensitivity Reactions

The basis of which is the fact that degradation products of
penicillin combine with host protein and become antigenic.

30. Adverse effects

Cont…
In approximate order of decreasing frequency,
manifestations of allergy to penicillins include
maculopapular rash, urticarial rash, fever,
bronchospasm, vasculitis, serum sickness, exfoliative
dermatitis, Stevens-Johnson syndrome, and anaphylaxis

The incidence of such reaction is 5-8% of the Pts
receiving Penicillins

31. Adverse effects

Cont…
Very high doses of penicillin G can cause
seizures in kidney failure.

Pain at I.M injection site

Nausea on oral ingestion

Thromboplebitis of injected vein

32. Penicillin V

Orally active

Used for the treatment of bacteremia and oral
infections

Higher minimum bactericidal concentration

33. Semisynthetic penicillins

The major draw backs of benzylpenicillin are:

Inactivation by gastric acid

Short duration of action

Poor penetration into the CSF

Narrow spectrum of activity

Susceptibility to Penicillinase

Development of resistance

Possibility of anaphylaxis

34. Penicillinase-resistant penicillins
(antistaphylococcal penicillins)

These congeners have side chains that protect the beta
lactam ring from attack by staphylococcal penicillinase

Indicated in infections caused by penicillinase producing
staphylococci (drugs of choice, except in MRSA)

Methicillin, Cloxacillin

Oxacillin, Nafcillin, Dicloxacillin

35. Penicillinase-resistant penicillins
(antistaphylococcal penicillins)Cont…
Methicillin:
Acid
Not
labile
used clinically, except to identify resistant
strains
MRSA
is susceptible to Vancomycin/linezolid and
rarely Ciprofloxacin

36. Penicillinase-resistant penicillins
(antistaphylococcal penicillins)Cont…
Cloxacillin:
Acid
resistant
More
active than methicillin
Less
active against PnG sensitive organisms: should not be used as
its substitute
Incompletely
>90%
but dependably absorbed (oral route)
protein bound, eliminated primarily by kidney, also partly by
liver
Plasma
half life is about 1hr

37. Extended spectrum penicillins

Active against a variety of gram-negative bacilli as well

Can be grouped according to their spectrum of activity
1. Aminopenicillins:
Ampicillins:

Active against all organisms sensitive to PnG; in
addition, many gram-negative bacilli

38. Extended spectrum penicillins
Cont…

39. Extended spectrum penicillins
Cont…
Pharmacokinetics:
Acid
resistant
Oral
absorption is incomplete but adequate
Primary
excretion is kidney, partly enterohepatic circulation occurs
Plasma
half life is 1hr
Uses:
UTI,
RTI, Meningitis, Gonorrhoea, typhoid fever, bacillary dysentery,
Cholisystitis, Subacute bacterial endocarditis and Septicemias

40. Extended spectrum penicillins
Cont…
Adverse effects:
Diarrhoea
Rashes
Hypersensitivity
Interactions:
Hydrocortisone
OC
–inactivates ampicillin if mixed in the I.V solution
–failure of oral contraception
Probenecid
–retards renal excretion

41. Extended spectrum penicillins
Cont…

Bacampicillin –ester prodrug of ampicillin

Talampicillin, Pivampicillin and Hetacillin are other Prodrugs of
ampicillin
Amoxicillin:


Close congener of ampicillin but not a prodrug
Similar to it in all aspects except:




Better oral absorption
Higher and sustained blood levels are produced
Incidence of diarrhoea is lower
Less effective against Shigella and H. influenzae

42. Extended spectrum penicillins
Cont…
2. Carboxypenicillins (Carbenicillin, Ticarcillin)
and
3. Ureidopenicillins (Piperacillin)

43. Extended spectrum penicillins
Cont…

These are called antipseudomonal penicillins

Piperacillin is more potent among these

Carbenicillin is less effective against Salmonella, E. Coli and
enterobacter but not active against Klebshiella and gram-positive
cocci

Piperacillin has good activity against Klebshiella, and is used mainly
in neutropenic/ immunocompromised patients having serious gramnegative infections and in burns

44. Beta-lactamase inhibitors

Clavulanic acid, Sulbactam
and Tazobactam

They contain beta-lactam ring
but themselves, do not have
significant antibacterial activity

45. Beta-lactamase inhibitors
Clavulanic acid :
Obtained
Called
from Streptomyces clavuligerus
a suicide inhibitor
Pharmacokinetics
matches amoxicillin with which it is used
Sulbactam:
Semisynthetic
Related
It
beta-lactamase inhibitor
chemically as well as in activity to clavulanic acid
is also a progressive inhibitor
Combined
with ampicillin
Cont…

46. Beta-lactamase inhibitors
Cont…
Tazobactam:
Similar
to Sulbactam
Pharmacokinetics
matches with Piperacillin with which it is used for
used in severe infections like peritonitis, pelvic/urinary/respiratory
infections
However,
the combination is not effective against piperacillin-resistant
Pseudomonas

47. They are available only in fixed combinations with
specific penicillins:
Ampicillin
+ Sulbactam (1g+0.5g I.V/I.M inj)
Amoxycillin
+ Clavulanic acid (250mg+125mg tab)
Piperacillin
+ Tazobactam sodium (2g+0.25g I.V/I.M
inj)