Protein Synthesis Inhibitors

What is the bacterial ribosome structure and what are its subunits?

70S ribosome made up of 30S and 50S subunits

What is the human ribosome structure and what are its subunits?

80S ribosome made up of 40S and 60S subunits

Why are protein synthesis inhibitors selectively toxic to bacteria?

They target bacterial 30S or 50S subunits which are structurally different from human 40S and 60S subunits

What are the 4 consequences of ribosomal inhibition by antibiotics?

Failure to initiate protein synthesis, failure of elongation, misreading of tRNA, and breakup of polysomes

Name the classes of protein synthesis inhibitors

Tetracyclines, Chloramphenicol, Aminoglycosides, Macrolides, Clindamycin, Oxazolidinones

What does the name tetracycline refer to structurally?

Four fused six-sided rings — tetra (four) + cycline (rings)

What was the first tetracycline and where was it isolated from?

Chlortetracycline — isolated from Streptomyces aureofaciens

Classify tetracyclines by duration of action

Short-acting: Tetracycline, Oxytetracycline; Intermediate: Demeclocycline, Lymecycline; Long-acting: Doxycycline, Minocycline

What is the mechanism of action of tetracyclines?

Reversibly bind to the 30S ribosomal subunit and interfere with tRNA binding to the acceptor site of mRNA, stopping peptide chain elongation

Are tetracyclines bactericidal or bacteriostatic?

Bacteriostatic

Why are tetracyclines non-toxic to human cells?

Active transport carrier is absent in mammalian cells and they do not bind to mammalian 40S or 60S ribosomal subunits

What divalent cations impair tetracycline absorption?

Ca²⁺, Mg²⁺, Fe³⁺, and Al³⁺ — form non-absorbable chelate complexes

Why should tetracyclines not be taken with dairy products or antacids?

They contain Ca²⁺ and Mg²⁺ which chelate tetracyclines and reduce absorption

Which tetracyclines are NOT affected by food absorption?

Doxycycline and Minocycline

Why are doxycycline and minocycline safe in renal impairment?

They are excreted primarily through bile rather than the kidneys

Which tetracycline enters CSF, saliva, and tears?

Minocycline

What is the significance of minocycline entering saliva?

It can eradicate the meningococcal carrier state — but is not used as prophylaxis due to adverse effects of vertigo and dizziness

What drug interaction do tetracyclines have with warfarin?

Tetracyclines inhibit vitamin K-producing intestinal flora, potentiating the anticoagulant effect of warfarin

Where do tetracyclines concentrate in the body?

Liver, kidney, spleen, skin, and tissues undergoing calcification — teeth, bones, tumours with high calcium content

Why are tetracyclines contraindicated in children and pregnant women?

They cross the placenta and enter fetal bones and dentition, causing retarded bone growth and permanent tooth staining

Name the 4 mechanisms of tetracycline resistance

1) Decreased cell permeability, 2) Increased efflux via tet(A) and tet(B), 3) Ribosomal protection via tet(M) and tet(O), 4) Enzymatic degradation via tet(X)

What enzyme degrades tetracycline in enzymatic resistance?

Tet(X) — a flavoprotein monooxygenase that inactivates tetracycline by monohydroxylation

What is the clinical significance of tetracycline resistance via plasmids?

Because of multi-valent plasmids, tetracycline resistance often indicates co-resistance to aminoglycosides, sulfonamides, and chloramphenicol

What are the adverse effects of tetracyclines?

Retarded bone growth, teeth staining, hepatotoxicity, nephrotoxicity, Fanconi syndrome (expired drug), phototoxicity, superinfections (candidiasis, pseudomembranous colitis)

What is Fanconi syndrome in the context of tetracyclines?

Proximal tubule damage caused by using expired tetracyclines — breakdown products are nephrotoxic

What is Tigecycline and what class does it belong to?

A glycylcycline — a newer generation tetracycline derived from minocycline

How was Tigecycline structurally modified from minocycline?

N,N-dimethylglycylamido side chain added at position 9 of minocycline

How is Tigecycline more potent than regular tetracyclines?

It binds the 30S subunit 20 times more effectively

Why is Tigecycline active against tetracycline-resistant strains?

Its structural modification renders it resistant to efflux pump-mediated resistance

What organisms is Tigecycline active against?

MRSA, multidrug-resistant S. pneumoniae, N. gonorrhoeae, and penicillin-resistant pneumococci

Does Tigecycline require dose adjustment in renal or hepatic disease?

No — eliminated by biliary excretion and not metabolized by CYP450

What organism produces Chloramphenicol?

Streptomyces venezuelae

What part of Chloramphenicol is responsible for antibacterial activity and bitter taste?

The nitrobenzene ring

What is the mechanism of action of Chloramphenicol?

Reversibly binds to the 50S ribosomal subunit and inhibits peptide bond formation by blocking peptidyl transferase activity

Against which organisms is Chloramphenicol bactericidal?

H. influenzae and N. meningitidis

What happens at high doses of Chloramphenicol?

It inhibits the host cell's 60S ribosomal subunit — causing host toxicity

Does Chloramphenicol penetrate the CSF?

Yes — in sufficient therapeutic quantities (unlike tetracyclines)

How is Chloramphenicol metabolized?

By glucuronide conjugation in the liver

Why does Chloramphenicol require dose adjustment in neonates?

Neonates have immature liver enzymes and cannot perform adequate glucuronide conjugation, leading to drug accumulation

What is the principal mechanism of Chloramphenicol resistance?

Plasmid-mediated production of chloramphenicol acetyl transferase — metabolizes the drug to an inactive metabolite

What is Grey Baby Syndrome?

A life-threatening toxicity of Chloramphenicol in neonates — caused by inadequate glucuronidation and drug accumulation, presenting with poor feeding, abdominal distension, cardiovascular collapse, cyanosis (grey colour), and death

Why does Chloramphenicol cause bone marrow suppression?

Inhibition of host mitochondrial ribosomes — mitochondria have 70S ribosomes similar to bacteria

What haematological adverse effects does Chloramphenicol cause?

Dose-dependent reversible bone marrow suppression, aplastic anaemia, agranulocytosis, thrombocytopenia, and idiosyncratic aplastic anaemia

What is the difference between dose-dependent and idiosyncratic aplastic anaemia from Chloramphenicol?

Dose-dependent suppression is reversible and related to dose; idiosyncratic aplastic anaemia is rare, unpredictable, and can occur with any dose

What is the structure of Macrolides?

Macrocyclic lactone ring with deoxy sugars attached

What is the mechanism of action of Macrolides?

Reversibly bind to the 50S ribosomal subunit, prevent translocation of the ribosome along mRNA, block the polypeptide exit tunnel, and cause dissociation of peptidyl-tRNA

Under what conditions is macrolide activity enhanced?

Alkaline pH

What cardiac adverse effect do Macrolides cause?

QT interval prolongation by affecting potassium ion channels — can cause Torsades de Pointes and sudden death

Are Macrolides bactericidal or bacteriostatic?

Bacteriostatic at normal concentrations, bactericidal at higher concentrations

Why does Erythromycin require enteric coating?

It is destroyed by gastric acid

Name the three mechanisms of macrolide resistance

1) Reduced permeability or active efflux, 2) Production of esterase that hydrolyzes macrolides, 3) Ribosomal protection by chromosomal mutation or methylase

How was Azithromycin derived from Erythromycin?

A methylated nitrogen was added into the lactone ring

What is the tissue half-life of Azithromycin?

2–4 days — allowing once-daily dosing and shorter treatment courses

Does Azithromycin inhibit CYP450 enzymes?

No — fewer drug interactions than Erythromycin

What is Azithromycin particularly highly active against?

Chlamydia species

How was Clarithromycin derived from Erythromycin?

A methyl group was added to the erythromycin structure

What is Clarithromycin more active against compared to Erythromycin?

Mycobacterium avium complex, M. leprae, T. gondii, and H. influenzae

What are Ketolides and how do they differ from macrolides?

Semisynthetic 14-membered ring macrolides where a 3-keto group replaces the cladinose sugar — making them poor substrates for efflux pumps and allowing activity against macrolide-resistant strains

What are Ketolides indicated for?

Community-acquired bacterial pneumonia (CAP) only

What is the major adverse effect of Ketolides?

Risk of hepatitis and liver failure

What is Clindamycin and where is it derived from?

A chlorine-substituted derivative of lincomycin, derived from Streptomyces lincolnensis

What is the mechanism of action of Clindamycin?

Same as macrolides — binds to the 50S ribosomal subunit

Why should Clindamycin not be co-administered with Macrolides?

They compete for the same binding site on the 50S subunit — antagonism

What is Clindamycin best used for and why?

Soft tissue infections and abscesses — penetrates well into these tissues and into phagocytic cells

What serious adverse effect is classically associated with Clindamycin?

Pseudomembranous colitis caused by C. difficile overgrowth

Does Clindamycin penetrate the CSF or brain?

No — does not penetrate the CNS

What is the unique mechanism of Oxazolidinones like Linezolid?

Prevents formation of the ribosome initiation complex — unique binding to 23S ribosomal RNA of the 50S subunit

Why do Oxazolidinones have no cross-resistance with other antibiotics?

Their binding site is unique — no other antibiotic class targets the same site

What is the oral bioavailability of Linezolid?

100%

Against which organisms is Linezolid bactericidal?

Streptococci — it is bacteriostatic against most others

What additional infection can Linezolid treat?

Mycobacterium tuberculosis

What are the haematological adverse effects of Linezolid?

Thrombocytopenia, anaemia, and neutropenia

What is the structure of Aminoglycosides?

A hexose ring (streptidine or 2-deoxystreptamine) with amino sugars attached by glycosidic linkages

Name six examples of Aminoglycosides

Streptomycin, Neomycin, Kanamycin, Amikacin, Gentamicin, Tobramycin

What is the mechanism of action of Aminoglycosides?

Irreversibly bind to the 30S ribosomal subunit causing: interference with initiation complex, misreading of mRNA, and breakup of polysomes into nonfunctional monosomes

Are Aminoglycosides bactericidal or bacteriostatic?

Bactericidal — and irreversible inhibitors

Why do aminoglycosides have low activity against anaerobes?

Anaerobes lack the oxygen-requiring active transport system needed to bring aminoglycosides into the cell

Why do Aminoglycosides and Beta-lactams act synergistically?

Beta-lactams damage the cell wall, enhancing aminoglycoside penetration into the cell

What is the principal mechanism of aminoglycoside resistance clinically?

Transferase enzyme inactivation — adenylylation, acetylation, or phosphorylation of the drug

Are Aminoglycosides well absorbed orally?

No — very poorly absorbed; almost the entire oral dose is excreted in faeces

What is the serum half-life of Aminoglycosides?

2–3 hours

What is the post-antibiotic effect of Aminoglycosides?

Antibacterial activity persists beyond measurable drug levels — allows once-daily dosing and reduces nephrotoxicity

What are the auditory-toxic Aminoglycosides?

Neomycin, Kanamycin, Amikacin — cause tinnitus and hearing loss

Which Aminoglycoside is most vestibulotoxic?

Gentamicin — causes vertigo, ataxia, and loss of balance

What combination should be avoided with Aminoglycosides due to synergistic nephrotoxicity?

Loop diuretics or vancomycin

What are the most nephrotoxic Aminoglycosides?

Neomycin, Tobramycin, Gentamicin

What neuromuscular adverse effect can Aminoglycosides cause?

Curare-like neuromuscular blockade leading to respiratory paralysis

How is Aminoglycoside-induced neuromuscular blockade reversed?

With calcium gluconate or neostigmine

What is Spectinomycin and what is it used for?

An aminocyclitol antibiotic structurally related to aminoglycosides (but without amino sugars) — used as an alternative treatment for drug-resistant gonorrhoea or in penicillin-allergic patients

Compare tetracyclines and aminoglycosides at the 30S subunit

Both bind 30S — but tetracyclines bind reversibly (bacteriostatic) while aminoglycosides bind irreversibly (bactericidal)

Which protein synthesis inhibitors target the 30S subunit?

Tetracyclines and Aminoglycosides

Which protein synthesis inhibitors target the 50S subunit?

Chloramphenicol, Macrolides, Clindamycin, and Oxazolidinones