1. Cell Wall Synthesis Inhibitors (Penicillins)
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture 2
February 02, 2013

2. Targets of Antibiotic Inhibition of cell wall synthesis
Inhibition of protein synthesis
Inhibition of nucleic acid replication and transcription
Injury to plasma membrane
Inhibition of synthesis of essential metabolites

3. Targets of Antibiotic

4. Classification of Cell Wall Synthesis Inhibitor
Cell wall synthesis inhibitor antibiotics have two types
β-Lactam antibiotic
Other antibiotic

5. β-Lactam Antibiotic β-Lactam antibiotics have four classes Penicillin
Cephalosporin
Carbapenem
Monobactam

6. Penicillin Penicillin is most widely effective antibiotic
Few names of Penicillin class of antibiotic
Amoxicillin
Ampicillin
Dicloxacillin
Oxacillin
Penicillin G
Penicillin V

7. Why Penicillin called β-Lactam Antibiotics?
Name of this antibiotic is because of the presence of β-lactam ring
This ring can be cleaved by β-lactamase enzymes produced by bacteria
This class of antibiotics kill bacteria by inhibiting bacterial cell wall synthesis

8. Structure of Penicillin
Nucleus contains a β-lactam and a thiazolidine ring
Metabolic transformation or chemical alteration of penicillin nucleus causes loss of all significant antibacterial activity
Side chain affects the antimicrobial spectrum, stability to stomach acid, and susceptibility to bacterial degradative enzymes C NH CH O N
CH3
COOH S
b-lactam
Thiozolidine
Site of penicillinase action

9. Penicillin: History
1928: Alexander Fleming working at St Mary's Hospital in London first discovered penicillin
1940: Extracted and antibacterial effects analyzed
1941: First antibiotic used clinically

10. Penicillin: Mechanism of Action
Interfere with the last step of bacterial cell wall
Cell lysis can occur, either through osmotic pressure or through the activation of autolysins
The success of a penicillin in causing cell death is related to the antibiotic's size, charge, and hydrophobicity
Penicillin are effective against rapidly growing organisms that synthesize a peptidoglycan cell wall
Consequently, they are inactive against organisms devoid of this structure, e.g., mycobacteria, protozoa, fungi, and viruses

11. Penicillin: Mechanism of Action, continued..
Details mechanisms of action:
1. Penicillin-binding proteins:
Penicillin inactivate numerous proteins on the bacterial cell membrane
These penicillin-binding proteins (PBPs) are involved in the synthesis of the cell wall
Interfere with the last step of bacterial cell wall

12. Penicillin: Mechanism of Action, continued..
2. Inhibition of transpeptidase
Inhibit this transpeptidase-catalyzed reaction, thus hindering the formation of cross-links essential for cell wall integrity
3. Production of autolysins
The antibacterial effect of a penicillin is the result of both inhibition of cell wall synthesis and destruction of existing cell wall by autolysins
An autolysin is an enzyme that hydrolyzes (and breaks down) the components of a biological cell or a tissue in which it is produced

13. Penicillin: Pharmacokinetic Aspects
Administration: Route of administration is determined by the stability of the drug to gastric acid and by the severity of the infection, e.g., oral, i.v., combine with other antibiotic
Absorption: Most of the penicillin are incompletely absorbed after oral administration. However, amoxicillin is almost completely absorbed
Distribution: Distribute well throughout the body. Penicillin cross the placental barrier
Excretion: Excretion is through the tubular secretary system of the kidney as well as by glomerular filtration

14. Penicillin: Adverse Effects
Penicillins are among the safest drugs. However, the following adverse reactions may occur
Hypersensitivity is the most important adverse effect
Diarrhea is a common problem
Penicillins are irritating to neuronal tissue
Hypersensitivity refers to undesirable reactions produced by the normal immune system

15. Classification: Based on Antibacterial Spectrum
Penicillin with a narrow antibacterial spectrum:
Acid labile penicillin
Benzylpenicillin (Penicillin G)
Acid stable penicillin
Phenoxymethylpenicillin
Antistaphylococcal penicillin
Cloxacillin
Extended spectrum penicillin:
Ampicillin
Amoxycillin

16. Penicillin G Drug of choice for: Adverse effects: Shortcomings:
Streptococcal, pneumococcal, gonococcal infections, anthrax, diphtheria, syphilis, tetanus
Adverse effects:
Anaphylaxis can occur (1 in 100,000 injections), always enquire about previous reaction before administration
Skin rashes
Shortcomings:
Acid labile, inactivated in gastric acid
Short half-life, frequent injections are required
Narrow antibacterial spectrum
Anaphylaxis is an acute multi-system severe type I hypersensitivity allergic reaction

17. Ampicillin/Amoxycillin
Uses:
Effective against most strains of Escherichia coli, Haemophilus influenza and Salmonella
Used for various chest infections, urinary tract infections
Amoxycillin is more potent than ampicillin
Both are susceptible to β-lactamases
Adverse effects:
Rashes are common and may appear after dosing has stopped
Pharmacokinetics:
Half life 1.5 h
Renal excretion

18. Resistance to Penicillin
Mechanism:
Natural resistance to the penicillins occurs in organisms that either lack a peptidoglycan cell wall or have cell walls that are impermeable to the drugs
β-lactamase enzymes hydrolyzes the β-lactam ring, which results in loss of bactericidal activity
Decreased penetration of the antibiotic through the outer cell membrane prevents the drug from reaching the target PBPs