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Major sites for action of antibiotics

ANTIMICROBIAL AGENTS AFFECTING
BACTERIAL PROTEIN SYNTHESIS

April 3, 2022

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal
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Bacterial protein synthesis Bacterial protein synthesis

 1. The elements of bacterial protein synthesis
are
 A ribosome (with 3 binding sites of for tRNA: P, A and
E sites)
 Messenger RNA (mRNA): with codon
 Transfer RNA (tRNA): with anticodon

 A tRNA with growing peptide chain is in the P

site, bound by codon-anticodon recognition
(i.e. complementary base-pairing)

 The incoming tRNA carries valine, covalently

linked.
Book: Rang & Dale’s Pharmacology, 7th edition,

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Bacterial protein synthesis Bacterial protein synthesis

 2. Binding of incoming tRNA to A site  3. Transpeptidation
 Peptide chain of
tRNA at P site is
transferred to the
tRNA on A site

 tRNA at P site has

been discharged

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Bacterial protein synthesis Bacterial protein synthesis

 Translocation  The discharged tRNA at E site is ejected.
 Ribosome moves on  A new tRNA with new amino acid
one codon, relative to attached (M) with relevant anticodon,
mRNA attaches to A site
 The discharged tRNA  And the whole process is repeated.
in now transferred
from the P site to E
site
 The tRNA with
growing peptide is
translocated from A
site to P site
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Drugs affecting bacterial protein synthesis

1. Tetracycline:
 Competition with tRNA for the A site
2. Chloramphenicol
 Inhibition of transpeptidation
3. Aminoglycosides:
 Gentamicin, Amikacin
 Misreading of codon: anticodon
4. Macrolides: inhibition of translocation
5. Puromycin: Premature termination of peptide
chain
6. Spectinomycin and Fusidic acid and : inhibition
of translocation

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1. TETRACYCLINES Classes
 Four cyclic anthracycline ring structure  Group 1: Shorter acting (6-10hrs half life)
 Tetracycline, Chlortetracycline,
Oxytetracycline

 Group 2: Intermediate acting (12-13hrs half

life)
 Demeclocycline, Methacycline

 All are obtained from soil actinomycetes.

 Group 3: Long acting (18-20hrs half life)
 Broad spectrum antibiotics – orally  Doxycycline, Minocycline
active

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Mechanism Mechanism
 Bacteriostatic  “Energy dependent active transport” process
concentrates tetracycline intracellularly in all
 Inhibit protein synthesis susceptible organism
 By binding to 30S ribosome in
susceptible organism  In gram negative bacteria : passive diffusion
 Interferes for attachment of aminoacyl- through “porin channels”
t-RNA to A site of mRNA-ribosome
complex  Selective activity against microbes
1. Carrier for active transport is absent in host
 As a result, peptide chain fails to grow mammalian cells
 Thus, bacterial protein synthesis stops. 2. Does not bind to mammalian 80S ribosome (60S /
40S)

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Antimicrobial spectrum Four mechanisms to tetracycline resistance

 Highly active
Chlamydia (Pneumonia)

 Spirochetes
1. Decreased cell permeability of drug
 Mycoplasma pneumoniae (atypical pneumonia)
 Rickettsia (Rocky mountain spotted fever) 2. Increased drug efflux by energy
 Quite Sensitive organisms are
 Gram positive bacilli dependent process: most important
 Clostridia and other anaerobes, Listeria, Corynebacterium,
 Propionibacterium acnes, B. anthracis
3. Ribosomal protection
 Gram negative bacilli
 V. cholerae, Yersinia pestis, Y. enterocolitica,
 Campylobacter, Helicobacter pylori, Brucella, and many 4. Enzymatic inactivation
anaerobes.
 All Cocci are resistant
 Resistant G-ve bacilli: E.coli, P. aeruginosa, Klebsiella,
Salmonella

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Clinical Uses Pharmacokinetics

 Absorption: Variable,
1. Cholera: V. cholera  30% Chlortetracycline
2. Brucellosis: Brucella abortus
 60 % Oxytetra, Demeclo, tetracycline
3. Plague: Y. pestis
 90 % Mino and doxycycline
4. Relapsing fever
5. UTI, Community acquired pneumonia  Food retards absorption (except G III)
6. Acne, peptic ulcer and COPD  Chelation due to altered pH
7. Chlamydial Urethritis, Endocervicitis
 Dairy products, Ca2+: Chelation
8. Atypical pneumonia: M. Pneumonia
9. Rickettsial infection: Rocky mountain spotted  Antacids with Mg2+, Al3+ or NaHCO3: Chelation
fever
 Fe3+ Chelation
10. Amoebiasis.
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Pharmacokinetics Adverse effects

1. Staining of deciduous and permanent teeth
 Wide distribution (Except CSF) 2. Retardation of bone growth
 Crosses placental barrier 3. Nephrotoxic (except G-III class)
 Protein binding: G-I (20-60%), G-II (40-80%), G-III 4. Fanconi’s Syndrome
(80-95%)  Renal toxicity due to use of tetracycline preparation
 Half life: 6, 12, 18hrs for G-I to G-III class after expiry date
 Deposits in tissue with high calcium  Reason: Degraded products such as epitetracycline,
 Teeth, bones, tumor-gastric anhydrotetracycline and epianhydrotetracycline
 Metabolize in liver and concentrated in bile damages PCT
5. Diabetes insipidus by demeclocycline which antagonize
 Secreted in breast milk also the ADH action
 Excreted in urine, except Doxy and minocycline 6. Superinfection:
(Biliary excretion)  Skin fungal infection (candida albicans)
 Diarrhoea (S. aureus and C. difficile) due to inhibition of
normal flora in intestine.
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Adverse effects Drug interactions

7. Vestibular toxicity
1. Divalent / trivalent cations
 Vertigo by Minocycline deposition in lipid tissue
 Causes chelation thus decrease TCs absorption
8. Hepatotoxicity, specially during pregnancy
 Jaundice, increased bilirubin
2. NaHCO3 by altering gastric pH reduces TCs
9. Photo-toxicity
absorption
 Sun burn like skin reaction: Demeclo and
doxycycline
 Distortion of nails sometimes 3. Enzyme inducers (eg.?) reduces serum levels
10.Irritating effects of TCs
 Phlebitis at the site of i.v.
 Pain at site of i.m. 4. TCs inhibit intestinal flora decreased Vit. K
 Epigastric burning: Nausea, vomiting with oral this may potentiate the action of
administration anticoagulants effects of warfarin

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Contraindications Newer tetracycline

 “Glycylcycline”: Tigecycline
1. Pregnant or lactating women, Why?  Minocycline analogue
 Mechanism: By binding to 30S subunit,
2. Renal impairment inhibits protein synthesis
 Two times potent than TCs
3. Hepatic insufficiency  Bacteriostatic against tetracycline
resistant cocci and bacilli
4. Child below 10Y  MDR Salmonella, Klebsiella, E.coli and P.
aeruginosa

5. Expired preparations
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Newer tetracycline 2. Chloramphenicol

 Spectrum  Natural Source: Streptomyces venezuelae
 MRSA  Mechanism of action
 Binds to 50S subunit of bacterial ribosome
 Vancomycin Resistant Enterococci
 S. pneumoniae  Inhibit transpeptidation, by interfering with transfer

 Others e.g. (similar to TCs including TCs of elongating peptide chain to the newly attached
resistant bacteria) aminoacyl-tRNA at rmRNA complex.

 Use: Skin, soft tissue and intra-  At high dose, toxic to host bone marrow cells

abdominal complicated infections  It also binds to host ribosome and

 Inhibit protein synthesis in bone marrow

 DI: rare
 Does not get metabolize be CytP450.
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2. Chloramphenicol 2. Chloramphenicol
 Bacteria develop resistance by  Antimicrobial spectrum
 Decreasing cell permeability of drug  Bacteriostatic action

 Enzymatic inactivation of drug through  Spectrum is similar to tetracycline: ?

acetyltransferase  ……………………………………………………………
 Ribosomal protection  Cidal action against N. meningitidis and
H. influenzae

 Anaerobic including B. fragilis (Abscess)

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2. Chloramphenicol 2. Chloramphenicol
 Clinical uses  Kinetic
 Meningitis : N. meningitides, H.
influenza, S. pneumoniae  Chloramphenicol palmitate convert into
 (Drug of choice is III generation chloramphenicol by pancreatic lipase
cephalosporins e.g. Ceftriaxone and
cefotaxime)  Oral and i.v. administration
 Typhoid fever: S. typhi, use declined due
to toxicity and resistance  Wide distribution including CSF
 Anaerobic infections: Pelvic and brain  Excreted by urine through glucuronide
abscess
conjugation
 Topically: Conjunctivitis and external ear
infection
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2. Chloramphenicol 2. Chloramphenicol
 Adverse effects  Drug interactions
 Bone marrow depression (dose related)  Paracetamol: increases bioavailability by
 Reduced platelets, WBCs and RBCs 28%
 Idiosyncratic: Anaemia  Chloramphenicol is an enzyme inhibitor
 Gray baby syndrome: due to absence of  Thus, increases the concentration of

glucuronide conjugation  Morphine: leading to respiratory depression

 Warfarin: leading to increased bleeding

 cyanosis, hypothermia, loss of hunger and CNS
symptoms

 Superinfection
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