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CELL WALL SYNTHESIS INHIBITORS

Antibiotics: Cell Wall Synthesis Inhibitors | Part 1 Medical Editor: Sohani Kashi Puranic

● Penicillin Binding Proteins (PBPs)

OUTLINE
o Bind to β- lactam antibiotics
I) OVERVIEW
● β- lactamase
II) BACTERIAL CELL WALL Breaks down β-lactam ring of β-lactam antibiotics
III) DRUGS INHIBITING CELL WALL SYNTHESIS (penicillin, cephalosporins) → Penicillin/ cephalosporin
can’t bind to PBP → drug is rendered ineffective →
IV) APPENDIX therefore, bacteria acquire resistance against β-lactam
V) REVIEW QUESTIONS antibiotics if they have β-lactamase
VI) REFERENCES ● Autolytic enzymes

I) OVERVIEW
● Some antimicrobial drugs selectively interfere with
synthesis of the bacterial cell wall—a structure that
mammalian cells do not possess
● The cell wall is composed of a polymer called
peptidoglycan that consists of glycan units joined to
each other by peptide cross-links
● The most important members of this group of drugs are
the β-lactam antibiotics (named after the β-lactam ring
that is essential to their activity), vancomycin, isoniazid
[Lippincott Illustrated Reviews: Pharmacology. 6th ed; p.483]

II) BACTERIAL CELL WALL

(A) TYPES OF BACTERIA

(1) GRAM POSITIVE BACTERIA
● Thick peptidoglycan layer (50-100 layers)
(2) GRAM NEGATIVE BACTERIA Figure 2. Gram Negative Bacterium
[Katzung BG: Basic & Clinical Pharmacology, 14e, 2018, p. 811, Fig. 43-3]
● Thin peptidoglycan layer (1-2 layers)
● Presence of an Outer Membrane (C) FYI
o Not present in gram positive bacteria- unique to
gram negative bacteria
Based on the mechanism of action, antibiotics can be classified
● Presence of Lipopolysaccharide as:
o Contains Lipid A/ Endotoxin 1. Bacteriostatic
o Also unique to gram negative bacteria • Prevent growth of bacteria
Figure 9. Gram-Positive and Gram-Negative Cell Walls • Bacteriostatic drugs inhibit protein synthesis
(B) STRUCTURE OF BACTERIAL CELL WALL 2. Bactericidal
• Kill the bacteria
● Peptidoglycan
o Each layer is a mucopeptide chain comprising of
alternating units of NAM (N-acetyl muramic acid)
and NAG (N-acetyl glucosamine molecules)
 NAM and NAG are derivatives of glucose
o Glycosidic bond
 Multiple (NAM-NAG) monomers are joined by
glycosidic bonds to form a peptidoglycan layer
o Pentapeptide side chain
 Extends from the NAM molecule
o Peptide bond
 The pentapeptide side chains are joined together
by a peptide bond
Catalyzed by transpeptidases

Figure 3. Effects of bactericidal and bacteriostatic drugs on the

growth of bacteria in vitro
[Lippincott Illustrated Reviews: Pharmacology. 6th ed, 2015, p. 474, Fig. 37.3]

Figure 1. Peptidoglycan Structure

CELL WALL SYNTHESIS INHIBITORS ANTIBIOTIC PHARMACOLOGY: NOTE #1. 1 of 4

 → therefore, cytoplasm becomes
III) DRUGS INHIBITING CELL WALL SYNTHESIS hyperosmolar
o Cell wall normally prevents rupture of
the cell due to endosmosis
o If cell wall is disrupted, water freely
enters into the cell, causing it to swell
up and rupture
• Bactericidal action is more effective in
actively proliferating bacteria
o As bacteria grow and multiply, they
actively synthesize new cell walls
o Hence, all cell wall synthesis
inhibitors are maximally effective in
actively proliferating cells

(iii) Adverse Effects

• Hypersensitivity reactions
o Type 1 Hypersensitivity Reaction
(allergy)
o Features: Urticaria, angioedema,
bronchospasm, anaphylaxis
(2) Amoxicillin

(i) Antibiotic Spectrum

Figure 4. Beta Lactams Overview
• Urinary Tract Infections
(A) BETA LACTAMS • Respiratory tract infections
• Meningitis
(1) Penicillin
• Salmonella
• Otitis media

(ii) Mechanism of Action

• Same as penicillin

(iii) Other Features

Amoxicillin is very susceptible to β-
AfraTafreeh.com• lactamase → therefore it needs to be
combined with β-lactamase inhibitors, like
Figure 5 Clavulanic Acid
[science.umd.edu] (3) Cephalosporins
(i) Antibiotic Spectrum:
• Acts on gram-positive and gram-negative
bacteria
1. Mostly act on gram- positive bacteria as
many gram-negative bacteria are
resistant
2. Resistance is acquired by presence of β-
lactamase and even the tightly-linked
peptidoglycan with outer membrane
• Streptococci
• Syphilis
Figure 6
(ii) Mechanism of Action: [science.umd.edu]
• Bactericidal
• Penicillin binds to PBP (Penicillin Binding
Proteins) → stimulates the PBPs (i) Classification
1. This further stimulates autolytic enzymes First Generation
in the bacteria → cleaves peptide bonds a. Cephalexin
and glycosidic bonds → peptidoglycan b. Cefazolin
structure isn’t formed → alters overall
Second Generation
structure of cell wall
a. Cefuroxime
2. Stimulation of PBP also inhibits the
transpeptidases → cross linking between Third Generation
peptidoglycan layers doesn’t take place a. Ceftriaxone
→ cell wall is disrupted b. Cefixime
• Disruption of cell wall causes water to leak Fourth Generation
into the bacterial cell → bacterial cell lysis a. Cefepime
o As the bacteria starts growing, it
Fifth Generation
needs various materials for growth

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 AfraTafreeh.com

• Resistant coagulase negative bacteria

(ii) Mechanism of Action

• Bactericidal
Figure 7. Cephalosporins • Vancomycin binds to the carboxy terminal
o 1st and 2nd generation cephalosporins are useful (-COO) of the peptide chain in peptidoglycan
in treatment of Gram-Positive bacterial → peptide bond between the two peptide
infections chains of different layers not formed → cell
o 3rd and 4th generation cephalosporins are useful wall disrupted → osmotic lysis of the
against gram-negative bacteria in addition to bacterial cell
gram positive bacteria
o 5th generation cephalosporins are useful against
MRSA (Methicillin Resistant Staphylococcus
aureus)
(C) ANTI-TUBERCULAR DRUG
(ii) Antibiotic Spectrum
Isoniazid
• Staphylococcus aureus
• Streptococcus pyogenes (i) Antibiotic Spectrum
• Pseudomonas aeruginosa
• Mycobacterium tuberculosis
• Meningitis
o Cell wall of Mycobacterium is
• Klebsiella pneumoniae
composed of mycolic acid residues
• Enterobacteria
o Cell wall synthesis is catalyzed by
(iii) Mechanism of Action the enzyme Mycolic Acid Synthase

• Same as penicillin (ii) Mechanism of Action

• Bind to different PBPs • Bactericidal
(B) GLYCOPEPTIDES • Isoniazid inhibits the enzyme, mycolic acid
synthase → cell wall synthesis is inhibited →
Vancomycin cell wall integrity altered → osmotic lysis of
bacterial cell
(i) Antibiotic Spectrum
• MRSA
• Clostridium difficile- causing
pseudomembranous enterocolitis

Figure 8. Glycopeptides

IV) APPENDIX

Figure 9. Gram-Positive and Gram-Negative Cell Walls

[Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e; 2018, p. 1030 Fig 57-2 A]

CELL WALL SYNTHESIS INHIBITORS ANTIBIOTIC PHARMACOLOGY: NOTE #1. 3 of 4

 Allergy to Penicillin causes which type of
V) REVIEW QUESTIONS Hypersensitivity reaction?
a. Type 1
What is the mechanism of action of
b. Type 2
Penicillin?
c. Type 3
a. Inhibits protein synthesis
d. Type 4
b. Inhibits cell wall synthesis
c. Causes leakage from cell membranes
d. Interferes with DNA function A 75-year-old male is admitted to the
hospital with severe pneumonia. He was
Which generation of cephalosporins is recently discharged from the hospital 6 days
useful for treating MRSA infections? ago after open heart surgery. The patient has
a. 2nd no known allergies. Which of the following
b. 3rd regimens is most appropriate for empiric
c. 4th coverage of methicillin resistant
d. 5th Staphylococcus aureus and Pseudomonas
Which drug needs to be combined with aeruginosa in this patient? [Hint: what type of
Clavulanic Acid (beta lactamase inhibitor) for bacteria is Pseudomonas aeruginosa? (Gram
efficient action? positive or gram negative?)]
a. Penicillin G a. Vancomycin + cefepime
b. Methicillin b. Vancomycin + cefazolin
c. Amoxicillin c. Penicillin + cefepime
d. Ceftriaxone d. Penicillin + cefepime

What is the type of action of beta lactam

CHECK YOUR ANSWERS
antibiotics on bacteria?
a. Bacteriostatic
VI) REFERENCES
b. Bactericidal
c. Both a & b
d. None ● Goodman & Gilman's: The Pharmacological Basis of
Therapeutics, 13e Brunton LL, Hilal-Dandan R, Knollmann BC.
Brunton L.L., & Hilal-Dandan R, & Knollmann B.C.(Eds.), Eds
Which drug is effective against (2018)
Mycobacterium tuberculosis? ● Lippincott Illustrated Reviews: Pharmacology. 6th ed.
a. Bacitracin Philadelphia, PA: Wolters Kluwer, (2015)
b. Isoniazid
● Katzung BG. Katzung B.G.(Ed.), Ed Bertram G. Katzung: Basic
c. Penicillin & Clinical Pharmacology, 14e. McGraw Hill (2018)
d. Cephalosporin AfraTafreeh.com
Which type of drug is to be avoided in
immunodeficient individuals? [Hint:
immunodeficient individuals are highly susceptible
to microbes in the body]
a. Bacteriostatic
b. Bactericidal
c. Both a & b
d. None

A 26-year-old male presents to the hospital

with a painless sore on his genitals that
started 2 weeks ago. He reports unprotected
sex with a new partner about 5 weeks ago. A
blood test confirms the patient has Treponema
pallidum. Which of the following is the drug of
choice for the treatment of this patient’s
infection as a single dose? [Hint: what disease
does Treponema Pallidum cause?]
a. Benzathine penicillin G
b. Ceftriaxone
c. Aztreonam
d. Vancomycin

A 17-year-old female presents to the

hospital with urinary frequency, urgency, and
fever for the past 3 days. Based on symptoms
and a urinalysis, she is diagnosed with a
urinary tract infection. Which of the following
is an appropriate oral option to treat the
urinary tract infection in this patient?
a. Cefazolin
b. Vancomycin
c. Isoniazid
d. Amoxicillin

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