Antibiotics Pharmacology - by ninja nerd notes.pdf

Antibiotics Pharmacology -
Cell wall inhibitors
Folic acid pathway inhibitors
Protein synthesis inhibitors
DNA & RNA synthesis inhibitors

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

CELL WALL SYNTHESIS INHIBITORS
Antibiotics: Cell Wall Synthesis Inhibitors | Part 1 Medical Editor: Sohani Kashi Puranic
OUTLINE
I) OVERVIEW
II) BACTERIAL CELL WALL
III) DRUGS INHIBITING CELL WALL SYNTHESIS
IV) APPENDIX
V) REVIEW QUESTIONS
VI) REFERENCES
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
● Thin peptidoglycan layer (1-2 layers)
● Presence of an Outer Membrane
o Not present in gram positive bacteria- unique to
gram negative bacteria
● Presence of Lipopolysaccharide
o Contains Lipid A/ Endotoxin
o Also unique to gram negative bacteria
Figure 9. Gram-Positive and Gram-Negative Cell Walls
(B) STRUCTURE OF BACTERIAL CELL WALL
● 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 1. Peptidoglycan Structure
● Penicillin Binding Proteins (PBPs)
o Bind to β- lactam antibiotics
● β- lactamase
Breaks down β-lactam ring of β-lactam antibiotics
(penicillin, cephalosporins) → Penicillin/ cephalosporin
can’t bind to PBP → drug is rendered ineffective →
therefore, bacteria acquire resistance against β-lactam
antibiotics if they have β-lactamase
● Autolytic enzymes

Figure 2. Gram Negative Bacterium
[Katzung BG: Basic & Clinical Pharmacology, 14e, 2018, p. 811, Fig. 43-3]
(C) FYI

Based on the mechanism of action, antibiotics can be classified
as:
1. Bacteriostatic
• Prevent growth of bacteria
• Bacteriostatic drugs inhibit protein synthesis
2. Bactericidal
• Kill the bacteria

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]
Last edited: 8/8/2021

2. 2 of 4
ANTIBIOTIC PHARMACOLOGY : NOTE #1. CELL WALL SYNTHESIS INHIBITORS

III) DRUGS INHIBITING CELL WALL SYNTHESIS

Figure 4. Beta Lactams Overview
(A) BETA LACTAMS
(1) Penicillin

Figure 5
[science.umd.edu]
(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
(ii) Mechanism of Action:
• Bactericidal
• Penicillin binds to PBP (Penicillin Binding
Proteins) → stimulates the PBPs
1. This further stimulates autolytic enzymes
in the bacteria → cleaves peptide bonds
and glycosidic bonds → peptidoglycan
structure isn’t formed → alters overall
structure of cell wall
2. Stimulation of PBP also inhibits the
transpeptidases → cross linking between
peptidoglycan layers doesn’t take place
→ cell wall is disrupted
• Disruption of cell wall causes water to leak
into the bacterial cell → bacterial cell lysis
o As the bacteria starts growing, it
needs various materials for growth
→ therefore, cytoplasm becomes
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
• Urinary Tract Infections
• Respiratory tract infections
• Meningitis
• Salmonella
• Otitis media
(ii) Mechanism of Action
• Same as penicillin
(iii) Other Features
• Amoxicillin is very susceptible to β-
lactamase → therefore it needs to be
combined with β-lactamase inhibitors, like
Clavulanic Acid
(3) Cephalosporins

Figure 6
[science.umd.edu]

(i) Classification
First Generation
a. Cephalexin
b. Cefazolin
Second Generation
a. Cefuroxime
Third Generation
a. Ceftriaxone
b. Cefixime
Fourth Generation
a. Cefepime
Fifth Generation

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


Figure 7. Cephalosporins
o 1
st
and 2
nd
generation cephalosporins are useful
in treatment of Gram-Positive bacterial
infections
o 3
rd
and 4
th
generation cephalosporins are useful
against gram-negative bacteria in addition to
gram positive bacteria
o 5
th
generation cephalosporins are useful against
MRSA (Methicillin Resistant Staphylococcus
aureus)
(ii) Antibiotic Spectrum
• Staphylococcus aureus
• Streptococcus pyogenes
• Pseudomonas aeruginosa
• Meningitis
• Klebsiella pneumoniae
• Enterobacteria
(iii) Mechanism of Action
• Same as penicillin
• Bind to different PBPs
(B) GLYCOPEPTIDES
Vancomycin
(i) Antibiotic Spectrum
• MRSA
• Clostridium difficile- causing
pseudomembranous enterocolitis
• Resistant coagulase negative bacteria
(ii) Mechanism of Action
• Bactericidal
• Vancomycin binds to the carboxy terminal
(-COO) of the peptide chain in peptidoglycan
→ peptide bond between the two peptide
chains of different layers not formed → cell
wall disrupted → osmotic lysis of the
bacterial cell



(C) ANTI-TUBERCULAR DRUG
Isoniazid
(i) Antibiotic Spectrum
• Mycobacterium tuberculosis
o Cell wall of Mycobacterium is
composed of mycolic acid residues
o Cell wall synthesis is catalyzed by
the enzyme Mycolic Acid Synthase
(ii) Mechanism of Action
• Bactericidal
• Isoniazid inhibits the enzyme, mycolic acid
synthase → cell wall synthesis is inhibited →
cell wall integrity altered → osmotic lysis of
bacterial cell





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]

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

V) REVIEW QUESTIONS
What is the mechanism of action of
Penicillin?
a. Inhibits protein synthesis
b. Inhibits cell wall synthesis
c. Causes leakage from cell membranes
d. Interferes with DNA function

Which generation of cephalosporins is
useful for treating MRSA infections?
a. 2
nd

b. 3
rd

c. 4
th

d. 5
th

Which drug needs to be combined with
Clavulanic Acid (beta lactamase inhibitor) for
efficient action?
a. Penicillin G
b. Methicillin
c. Amoxicillin
d. Ceftriaxone

What is the type of action of beta lactam
antibiotics on bacteria?
a. Bacteriostatic
b. Bactericidal
c. Both a & b
d. None

Which drug is effective against
Mycobacterium tuberculosis?
a. Bacitracin
b. Isoniazid
c. Penicillin
d. Cephalosporin

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
Allergy to Penicillin causes which type of
Hypersensitivity reaction?
a. Type 1
b. Type 2
c. Type 3
d. Type 4

A 75-year-old male is admitted to the
hospital with severe pneumonia. He was
recently discharged from the hospital 6 days
ago after open heart surgery. The patient has
no known allergies. Which of the following
regimens is most appropriate for empiric
coverage of methicillin resistant
Staphylococcus aureus and Pseudomonas
aeruginosa in this patient? [Hint: what type of
bacteria is Pseudomonas aeruginosa? (Gram
positive or gram negative?)]
a. Vancomycin + cefepime
b. Vancomycin + cefazolin
c. Penicillin + cefepime
d. Penicillin + cefepime

CHECK YOUR ANSWERS
VI) REFERENCES

● 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
(2018)

● Lippincott Illustrated Reviews: Pharmacology. 6th ed.
Philadelphia, PA: Wolters Kluwer, (2015)

● Katzung BG. Katzung B.G.(Ed.), Ed Bertram G. Katzung: Basic
& Clinical Pharmacology, 14e. McGraw Hill (2018)

5. Folic acid pathway inhibitors ANTIBIOTIC PHARMACOLOGY : NOTE #2. 1 of 3

2. FOLIC ACID PATHWAY INHIBITORS
Antibiotics: Folic Acid Pathway Inhibitors | Part 2 Medical Editor: Sohani Kashi Puranic
OUTLINE
I) OVERVIEW
II) FOLIC ACID PATHWAY
III) DRUGS INHIBITING FOLATE PATHWAY
IV) SUMMARY
V) APPENDIX
VI) REVIEW QUESTIONS
VII) REFERENCES


I) OVERVIEW
Enzymes requiring folate-derived cofactors are essential
for the synthesis of purines and pyrimidines
o They are precursors of RNA and DNA and other
compounds
o They are necessary for cellular growth and replication
o Therefore, in the absence of folate, cells cannot grow
or divide
To synthesize the critical folate derivative, tetrahydro folic
acid, humans must first obtain preformed folate in the
form of folic acid from the diet
In contrast, many bacteria are impermeable to folic acid
and other folates and, therefore, must rely on their ability
to synthesize folate de novo
o THE SULFONAMIDES (SULFA DRUGS) ARE A FAMILY
OF ANTIBIOTICS THAT INHIBIT THE DE NOVO
SYNTHESIS OF FOLATE IN BACTERIA
[Lippincott Illustrated Reviews: Pharmacology. 6th ed; p.517]
II) FOLIC ACID PATHWAY

Figure 1. Folic Acid Pathway
[Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e; 2018, p. 1013 Fig 56-2]

Para-amino benzoic acid (PABA) combines with
pteridine to form dihydro-pteroic acid in the presence
of the enzyme, Dihydropteroate synthase (DHPS)
Dihydro-pteroic acid is converted to Dihydrofolic acid
Dihydro-folic acid is reduced to Tetrahydro-folic acid
(THFA) by Dihydrofolate reductase (DHFR)
THFA is channeled into the purine and pyrimidine
synthesis pathway
Purine and Pyrimidines are essential components of
DNA and RNA
III) DRUGS INHIBITING FOLATE PATHWAY
(A) SULFONAMIDES
EX: SULFAMETHOXAZOLE
(1) Chemistry
Sulfonamides act as substrate analogues of PABA

Figure 2. Chemical Structure of Sulfonamide and PABA
[Katzung BG: Basic & Clinical Pharmacology, 14e, 2018, p. 835, Fig. 46-1]
(2) Mechanism of Action
Sulfonamides inhibit the enzyme dihydropteroate
synthase
This is an example of competitive inhibition
o Sulfonamides are structurally similar to PABA, as
seen in Figure 2
o Therefore, they inhibit the enzyme from binding to
PABA, thereby inhibiting the folic acid pathway
o Thus, DNA and RNA are not formed
o Essential metabolic processes required for growth do
not occur
o BACTERIOSTATIC
(3) Antibiotic Spectrum
Bacteriostatic against many gram-positive and gram-
negative bacteria
Toxoplasma
Nocardia
Streptococcus pyogenes
Urinary Tract Infections
(4) Adverse Effects

Can be managed by
alkalinizing urine




Rashes, urticaria, drug
fever




In G6PD deficiency




In newborn-
displacement of bilirubin
from plasma protein
binding sites


[Lippincott Illustrated Reviews: Pharmacology. 6th ed, 2015, p. 519, Fig.40.9]
Last edited: 8/15/2021

6. 2 of 3
ANTIBIOTIC PHARMACOLOGY : NOTE #2. Folic acid pathway inhibitors

(B) TRIMETHOPRIM
(1) Introduction
Trimethoprim is another folate antagonist
It is related to the antimalarial drug Pyrimethamine
(2) Mechanism of Action
Selectively inhibits bacterial dihydrofolate reductase
(DHFR)
o Dihydrofolic acid not converted to tetrahydro folic acid
o Purine, Pyrimidines not synthesized
o Affects synthesis of DNA, RNA
o BACTERIOSTATIC
(3) Antibiotic Spectrum
Same as Sulfamethoxazole
Gram-negative Enterobacteria
(C) COTRIMOXAZOLE -
BACTRIM
(1) Chemistry
Combination of
(i) Trimethoprim
(ii) Sulfamethoxazole
(2) Mechanism of Action
Blocks the folic acid pathway by Sequential Blockade
o Two drugs block successive steps in the same
pathway
(i) Sulfamethoxazole
o Inhibits dihydropteroate synthase
o Dihydro-pterioc acid not formed
(ii) Trimethoprim
o Inhibits dihydrofolate reductase
o THFA not formed
Individually, both these drugs are bacteriostatic, but the
combination is synergistic, and cotrimoxazole
becomes BACTERICIDAL

Figure 3. Sequential Blockade
[Katzung BG: Basic & Clinical Pharmacology, 14e, 2018, p. 811, Fig. 43-3]
(3) Antibiotic Spectrum
Broader spectrum-as it covers organisms sensitive to
both, sulfamethoxazole and trimethoprim
Urinary Tract Infections
Respiratory Tract Infections
Pneumocystis carinii
o In immunocompromised individuals
Bacterial diarrhea, dysentery
o E. coli, Shigella, non-typhoidal Salmonella
(4) Adverse Effects


IV) SUMMARY


Figure 4. Folic Acid Pathway Inhibitors






Rashes, stomatitis






Nausea, Vomiting,
Headache





Megaloblastic anemia
Hemolysis in G6PD
deficiency
Rarely, blood
dyscrasias
Neonatal
methemoglobinemia





[Lippincott Illustrated Reviews: Pharmacology. 6th ed, 2015, p. 522, Fig.40.14]

7. Folic acid pathway inhibitors ANTIBIOTIC PHARMACOLOGY : NOTE #2. 3 of 3

V) APPENDIX

Table 1. Summary of Folate Pathway Inhibitors
Drug Enzyme(s) inhibited Mechanism Antibiotic Spectrum
Sulfamethoxazole Dihydropteroate synthase Bacteriostatic
UTI
Toxoplasma
Nocardia
Trimethoprim Dihydrofolate reductase Bacteriostatic
Gram-negative
enterobacteria
Cotrimoxazole
Both, dihydropteroate synthase
and dihydrofolate reductase
Bactericidal
UTI
Respiratory Tract
Infections
Pneumocystis carinii



VI) REVIEW QUESTIONS
Sulfonamides inhibit which enzyme?
a. Dihydrofolate reductase
b. Dihydropteroate synthase
c. Dihydrofolate synthase
d. None of the above

Sulfonamides are structurally similar to:
a. Pteridine
b. Dihydrofolate
c. Tetrahydrofolate
d. PABA

Which drug is effective for treatment of
Pneumocystis carinii?
a. Bactrim
b. Pyrimethamine
c. Sulfadiazine
d. Trimethoprim

Combination of Trimethoprim and Sulfamethoxazole
is:
a. Synergistic
b. Antagonistic
c. Both a & b
d. None of the above
CHECK YOUR ANSWERS
VII) REFERENCES
● 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
(2018)

● Lippincott Illustrated Reviews: Pharmacology. 6th ed.
Philadelphia, PA: Wolters Kluwer, (2015)

● Katzung BG. Katzung B.G.(Ed.), Ed Bertram G. Katzung: Basic
& Clinical Pharmacology, 14e. McGraw Hill (2018)

8. PROTEIN SYNTHESIS INHIBITORS ANTIBIOTIC PHARMACOLOGY : NOTE #3. 1 of 4

3. PROTEIN SYNTHESIS INHIBITORS
Antibiotics: Protein Synthesis Inhibitors | Part 3 Medical Editor: Sohani Kashi Puranic
OUTLINE
I) OVERVIEW
II) BACTERIAL PROTEIN SYNTHESIS
III) DRUGS INHIBITING PROTEIN SYNTHESIS
IV) SUMMARY
V) APPENDIX
VI) REVIEW QUESTIONS
VII) REFRENCES


I) OVERVIEW
A number of antibiotics exert their antimicrobial effects by
targeting bacterial ribosomes and inhibiting bacterial
protein synthesis
The drugs described below inhibit bacterial protein
synthesis by binding to and interfering with ribosomes
Most are BACTERIOSTATIC, but a few are Bactericidal
against certain organisms
II) BACTERIAL PROTEIN SYNTHESIS
(A) BACTERIAL RIBOSOMES
(1) Structure
Composed of
o 30S subunit (small subunit)
o 50S subunit (large subunit)
(Mammalian ribosomes have 40S and 60S subunits)
(2) 50S Subunit
Comprised of the following sites during translation:
o A site- amino acyl/ acceptor site
o P site- peptidyl/ polypeptide site
o E site- exit site
(B) PROTEIN SYNTHESIS-TRANSLATION
(1) TRANSLATION
(i) Activation of tRNA
• Aka Charging Reaction
• tRNA is charged with amino acid
(ii) Initiation
(iii) Elongation
• Amino-acyl tRNA binds to A site
• Peptide bond formation
• Translocation of ribosome on mRNA
(iv) Termination
(v) Post-translational processing






Figure 1. Overview of Bacterial Translation
[khanacademy.org]
Last edited: 8/22/2021

9. 2 of 4
ANTIBIOTIC PHARMACOLOGY : NOTE #3. PROTEIN SYNTHESIS INHIBITORS

III) DRUGS INHIBITING PROTEIN SYNTHESIS
(A) MACROLIDES
(1) Drugs
(i) Erythromycin
(ii) Clarithromycin
(iii) Azithromycin
(2) Mechanism of Action
Inhibits bacterial protein synthesis
Combines with 50S ribosomal subunit
o Inhibits ribosome from moving along and reading
mRNA
o Inhibits elongation of peptide chain
o Functional protein not synthesized
BACTERIOSTATIC
o Inhibits specific cellular functions
o Inhibits various pathways from functioning

Figure 2. Mechanism of Action of Macrolides
[Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e; 2018, p. 1054 Fig 59-3]
(3) Antibiotic Spectrum & Uses
Pneumonia
o Legionella
o Mycoplasma
Helicobacter pylori
Gastrointestinal tract infections
o Campylobacter
Sexually Transmitted Diseases
o Chlamydia
o Gonorrhea
(4) Adverse Effects


Pain
Nausea
Anorexia





Can be seen in pregnant
women





Very high doses of
erythromycin


[Lippincott Illustrated Reviews: Pharmacology. 6th ed, 2015, p. 508, Fig.39.13]
(B) AMINOGLYCOSIDES
(1) Drugs
(i) Gentamycin
(ii) Tobramycin
(iii) Amikacin
(iv) Kanamycin
(2) Mechanism of Action
Inhibits bacterial protein synthesis
Binds to 30S ribosomal subunit
o Inhibits initiation of peptide formation
BACTERICIDAL
o Antibiotics that disrupt protein synthesis are generally
bacteriostatic
o However, aminoglycosides are unique in that they are
bactericidal
o The bactericidal effect of aminoglycosides is
concentration dependent


Figure 3. Mechanism of Action of Aminoglycosides
[Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e; 2018, p. 1040 Fig 58-2]

(3) Antibiotic Spectrum
Pseudomonas
Aerobic gram-negative bacteria
Enterobacteria (gram-negative)
(4) Uses
Urinary Tract Infection
Pneumonia
Meningitis
Peritonitis
(5) Adverse Effects


Drugs
concentrated in
labyrinthine fluid






Tubular
damage







Neuro-
muscular
blockade



[Lippincott Illustrated Reviews: Pharmacology. 6th ed, 2015, p. 505, Fig.39.9]

10. PROTEIN SYNTHESIS INHIBITORS ANTIBIOTIC PHARMACOLOGY : NOTE #3. 3 of 4

(C) TETRACYCLINES
(1) Drugs
(i) Tetracycline
(ii) Doxycycline
(iii) Minocycline
(2) Mechanism of Action
Inhibits bacterial protein synthesis
Binds to 30S ribosomal subunit
o Blocks amino-acyl tRNA from binding to A-site
o Failure of elongation of peptide chain
BACTERIOSTATIC
o Inhibits specific cellular functions
o Inhibits various pathways from functioning

Figure 4. Mechanism of Action of Tetracycline
[Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e; 2018, p. 1050 Fig 59-1]
(3) Antibiotic Spectrum & Uses
These are BROAD SPECTRUM antibiotics
Lyme disease
o Borrelia burgdorferi
Chlamydia
Acne
Rosaceae
Plague
o Yersinia pestis
Anthrax
Pneumonia
o Legionella
(4) Adverse Effects

[Lippincott Illustrated Reviews: Pharmacology. 6th ed, 2015, p. 502, Fig.39.6]
IV) SUMMARY

Figure 5. Summary

11. 4 of 4
ANTIBIOTIC PHARMACOLOGY : NOTE #3. PROTEIN SYNTHESIS INHIBITORS


V) APPENDIX
Table 1. Summary
Drug Ribosomal Subunit Targeted Mechanism Antibiotic Spectrum
Macrolide 50S Bacteriostatic
Pneumonia
H. pylori
GIT infections
STDs
Aminoglycoside 30S Bactericidal
Pseudomonas
Aerobic Gram-negative
bacteria
Enterobacteria
UTI
Pneumonia
Meningitis
Peritonitis
Tetracycline 30S Bacteriostatic
Lyme disease
Chlamydia
Pneumonia
Acne
Plague
Anthrax
VI) REVIEW QUESTIONS
Which drug is used to treat Acne?
a. Erythromycin
b. Daptomycin
c. Tetracycline
d. Amikacin

Which of the following antibiotic combinations have
the same site of action?
a. Clarithromycin and doxycycline
b. Amikacin and tetracycline
c. Vancomycin and erythromycin
d. Gentamycin and azithromycin

Which drug causes ototoxicity and nephrotoxicity?
a. Doxycycline
b. Gentamycin
c. Clarithromycin
d. Chloramphenicol

What does erythromycin bind to?
a. 50S subunit of ribosome
b. 40S subunit of ribosome
c. 30S subunit of ribosome
d. 80S subunit of ribosome

Which drug is used to treat Pneumonia?
a. Azithromycin
b. Gentamycin
c. Tetracycline
d. All of the above
VII) REFRENCES

● 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
(2018)

● Lippincott Illustrated Reviews: Pharmacology. 6th ed.
Philadelphia, PA: Wolters Kluwer, (2015)

● Katzung BG. Katzung B.G.(Ed.), Ed Bertram G. Katzung: Basic
& Clinical Pharmacology, 14e. McGraw Hill (2018)






























CHECK YOUR ANSWERS

12. DNA & RNA SYNTHESIS INHIBITORS ANTIBIOTIC PHARMACOLOGY : NOTE #4. 1 of 4

4. DNA & RNA SYNTHESIS INHIBITORS
Antibiotics: DNA & RNA Synthesis Inhibitors | Part 4 Medical Editor: Sohani Kashi Puranic

OUTLINE
I) OVERVIEW
II) DRUGS ACTING ON DNA & RNA
III) SUMMARY
IV) REVIEW QUESTIONS
V) REFERENCES

I) OVERVIEW
The drugs described below act on DNA and RNA and
inhibit their synthesis. As DNA and RNA are essential for
the survival of organisms, these drugs are
BACTERICIDAL.
The drugs discussed below are:
(i) Fluoroquinolones
(ii) Nitrofurantoin
(iii) Metronidazole
(iv) Daptomycin
(v) Rifampicin
II) DRUGS ACTING ON DNA & RNA
(A) FLUOROQUINOLONES
(1) Drugs
(i) Ciprofloxacin
(ii) Levofloxacin
(iii) Norfloxacin
(iv) Ofloxacin
(2) Mechanism of Action
TOPOISOMERASE ENZYME
Function:
o Relieves supercoils formed downstream from the DNA
replication site
o Alleviates the tension
Domains:
a. Cutting Domain
 Breaks phosphodiester bonds
 This relieves the tension of supercoils
b. Ligand Binding Domain
 Re-links the DNA fragments
Types:
o Gram-negative bacteria: TOPOISOMERASE II/ DNA
GYRASE
o Gram-positive bacteria: TOPOISOMERASE IV

Figure 1. Model of the formation of negative DNA supercoils by DNA
gyrase
DNA gyrase binds to two segments of DNA (1), creating a
node of positive (+) superhelix.
The enzyme then introduces a double-strand break in the DNA
and passes the front segment through the break (2).
The break is then resealed (3), creating a negative (–)
supercoil.
[Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e; 2018, p. 1016 Fig 56-3]
DNA Fragmentation
o Fluoroquinolones inhibit the enzyme
topoisomerase
o They act by:
 Stimulating the Cutting domain
 Inhibiting the Ligand-binding domain
o This means the DNA is broken down, but the
fragments are not rejoined

o This kills the bacteria, hence fluoroquinolones are
BACTERICIDAL
(3) Antibiotic Spectrum
Mostly act on gram negative bacteria, and some gram-
positive bacteria
(i) Highly susceptible:
(i) E. coli
(ii) H. influenzae
(iii) Salmonella typhi
(iv) Vibrio cholerae
(ii) Moderately susceptible:
(i) Pseudomonas aeruginosa
(ii) Mycoplasma
(iii) Mycobacterium tuberculosis
(iii) Low susceptibility:
(i) Streptococcus
(ii) MRSA
(4) Uses
Urinary Tract Infections
Pyelonephritis
Prostatitis
Osteomyelitis
Typhoid
2
nd
line drug for Tuberculosis
(5) Adverse Effects
[Lippincott Illustrated Reviews: Pharmacology. 6th ed, 2015, p. 517, Fig.40.5]
Last edited: 9/5/2021
Figure 2. Adverse Effects of Fluoroquinolones

13. 2 of 4
ANTIBIOTIC PHARMACOLOGY : NOTE #4. DNA & RNA SYNTHESIS INHIBITORS

(B) NITROFURANTOIN
(1) Drug
(i) Nitrofurantoin

(2) Mechanism of Action
Binds to enzyme Nitrofuran Reductase
o This results in conversion of Nitrofurantoin into
Reactive Intermediates

i. DNA Damage
ii. RNA Damage
iii. Protein Damage
o Since Nitrofurantoin inhibits the synthesis of DNA,
RNA and vital proteins, it is fatal to the bacteria-
BACTERICIDAL
(3) Antibiotic Spectrum
Gram negative and gram-positive coverage
(i) E. coli (gram negative)
(ii) Enterococci (gram positive)
(4) Uses
Urinary Tract Infections
(5) Adverse Effects
Nausea
Diarrhea
Hemolytic anemia in G6PD deficiency
(C) METRONIDAZOLE
(1) Drug
(i) Metronidazole

(2) Mechanism of Action
Binds to enzyme Nitro-Reductase
o This results in conversion of Metronidazole into
Active Metabolites



o Since Metronidazole causes DNA fragmentation, it is
fatal to the bacteria & certain protozoa-
BACTERICIDAL, AMOEBICIDAL
(3) Antibiotic Spectrum
Gram negative and gram-positive coverage
(i) H. pylori
(ii) Trichomonas vaginalis
Protozoa
(iii) Giardia lamblia
(iv) Entamoeba histolytica
(4) Uses
Peptic ulcer
Bacterial vaginosis
Giardiasis
Amoebiasis
(5) Adverse Effects
[Lippincott Illustrated Reviews: Pharmacology. 6th ed, 2015, p. 549, Fig.43.3]
(D) DAPTOMYCIN
(1) Drug
(i) Daptomycin
(2) Mechanism of Action
Creates a pore in the cell membrane


i. DNA Damage
ii. RNA Damage
iii. Protein Damage
o Since Daptomycin inhibits the synthesis of DNA, RNA
and vital proteins, it is fatal to the bacteria-
BACTERICIDAL
(3) Antibiotic Spectrum
Acts mainly on gram-positive bacteria
(i) Staphylococcus aureus


(4) Uses
Skin & soft tissue infections
Endocarditis
(5) Adverse Effects
Myopathy
Risk of rhabdomyolysis
(E) RIFAMPICIN
(1) Drug
(i) Rifampicin

(2) Mechanism of Action
Inhibits DNA-dependent RNA polymerase



Since Rifampicin inhibits transcription and in turn, the
synthesis of vital proteins, it is fatal to the bacteria-
BACTERICIDAL

Figure 3. Adverse Effects of Metronidazole

14. DNA & RNA SYNTHESIS INHIBITORS ANTIBIOTIC PHARMACOLOGY : NOTE #4. 3 of 4

(3) Antibiotic Spectrum
(i) Mycobacterium tuberculosis
(ii) Mycobacterium leprae
(iii) Hemophilus influenzae type- B
(4) Uses
Tuberculosis
Leprosy
H. influenzae meningitis
(5) Adverse Effects
Orange discoloration od urine, sweat and tears
Hepatotoxic
Nausea






III) SUMMARY

Figure 4. DNA & RNA Synthesis Inhibitors



Table 1.Summary of DNA & RNA Synthesis Inhibitors
1 2 3 4 5

15. 4 of 4
ANTIBIOTIC PHARMACOLOGY : NOTE #4. DNA & RNA SYNTHESIS INHIBITORS

IV) REVIEW QUESTIONS
1) What is the mechanism of action of Levofloxacin?
a) Inhibits 30S ribosomal subunit
b) Inhibits mRNA transcription
c) Inhibits enzyme nitro-reductase
d) Inhibits enzyme topoisomerase

2) Which drug is used as urinary antiseptic?
a) Nitroimidazole
b) Daptomycin
c) Nitrofurantoin
d) Gentamycin

3) Which drug(s) is/are used to treat tuberculosis?
a) Rifampicin
b) Isoniazid
c) Nitrofurantoin
d) Both a & b

4) Which drug is used to treat Amoebiasis?
a) Rifampicin
b) Daptomycin
c) Ciprofloxacin
d) Metronidazole

5) What is the mechanism of action of Rifampicin?
a) Inhibits DNA-dependent RNA Polymerase
b) Inhibits Nitro-reductase
c) Inhibits 50S ribosome
d) Forms pore in cell membrane

CHECK YOUR ANSWERS



























V) REFERENCES
● 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
(2018)

● Lippincott Illustrated Reviews: Pharmacology. 6th ed.
Philadelphia, PA: Wolters Kluwer, (2015)

● Katzung BG. Katzung B.G.(Ed.), Ed Bertram G. Katzung: Basic
& Clinical Pharmacology, 14e. McGraw Hill (2018)