PROTEIN SYNTHESIS INHIBITORS

(TDDM)

• Demeclocyline

• Doxycyline

• Minocycline

• Tetracycline

Tetracycline drugs

Tigecycline

Glycylcycline drug

(TANGS)

• Amikacin

• Gentamicin

• Neomycin

• Streptomycin

• Tobramycin

Aminoglycoside drugs

(ACE T)

• Azithromycin

• Clarithromycin

• Erythromycin

• Telithromycin

Macrolides/ketolides

Fidaxomicin

Macrocyclic

Clindamycin

Lincosamides

Linezolid

Oxazolidinones

• Chloramphenicol

• Quinupristin/dalfopristin

Protein synthesis inhibitors not belonging to tetracyclines, glycylcyclines, aminoglycosides, macrolides, macrocyclic, lincosamides, and oxazolidinones

They target bacterial ribosomes, which are structurally different from mammalian cytoplasmic ribosomes.

What is the general target of antibiotics that inhibit bacterial protein synthesis?

• Bacterial ribosomes: 30S + 50S subunits = 70S ribosome

• Mammalian cytoplasmic ribosomes: 40S + 60S subunits = 80S ribosome

What are the structural differences between bacterial and mammalian ribosomes?

Because bacterial ribosomes differ structurally from mammalian cytoplasmic ribosomes, allowing antibiotics to bind specifically to bacterial ribosomal subunits

Why do protein synthesis inhibitors have selective toxicity for bacteria?

Mitochondrial ribosomes

Which mammalian ribosomes resemble bacterial ribosomes and may be affected at high drug concentrations?

• chloramphenicol

• tetracyclines

The most specific toxicity concern of these drugs is that they can interact with mitochondrial ribosomes, leading to toxic effects because mitochondrial ribosomes are more similar to bacterial ribosomes

At high concentrations, they may bind mitochondrial ribosomes, disrupting host mitochondrial protein synthesis and causing toxicity.

Why can chloramphenicol and tetracyclines cause host toxicity despite being selective for bacterial ribosomes?

They inhibit bacterial protein synthesis by binding to ribosomal subunits.

What major mechanism do these antibiotics (chloramphenicol, tetracyclines, etc.) share?

They are protein synthesis inhibitors (ribosomal-targeting antibiotics).

What broad class do chloramphenicol and tetracyclines belong to based on their mechanism?

To exert antimicrobial effects by disrupting bacterial protein synthesis, thereby halting bacterial growth or killing the organism.

What is the fundamental therapeutic purpose of drugs that inhibit bacterial ribosomal function?

Tetracylcine

This protein synthesis inhibitor target the 30s subunit and prevent binding of tRNA to mRNA

Aminoglycosides

This protein synthesis inhibitor bind to the 30s subunit, distorting its structure and causing misreading of the mRNA

Erythromycin and clindamycin

This protein synthesis inhibitor bind to the 50s subunit, thus inhibiting translocation

Chloramphenicol

This protein synthesis inhibitor inhibits peptidyl transferase

Linezolid

This protein synthesis inhibitor binds the 23S ribosomal RNA preventing formation of the 70S initiation complex

Tetracycline

This consists of four fused rings with a system of conjugated double bonds.
Substitutions on these rings alter pharmacokinetics and spectrum of antimicrobial activity.

Tetracyclines are bacteriostatic, broad-spectrum protein synthesis inhibitors.

What is the drug classification of tetracyclines?

• Enter bacteria via passive diffusion and energy-dependent transport unique to bacterial inner cytoplasmic membranes.

• Concentrate intracellularly.

• Bind reversibly to the 30S ribosomal subunit → prevents tRNA from binding to the mRNA–ribosome complex.

• Result: inhibits bacterial protein synthesis.

Describe the mechanism of action of tetracyclines.

Through passive diffusion and an energy-dependent transport protein found only in bacterial inner cytoplasmic membranes.

How do tetracyclines enter susceptible bacteria?

Tetracyclines are commonly used for:

• Acne

• Chlamydia infections (doxycycline) → important drug of choice from the text

What are common clinical uses of tetracyclines?

Doxycycline (tetracycline)

Drug of choice for chlamydia infections

Lyme disease

• This is a spirochetal infection caused by Borrelia burgdorferi.

• The disease is transmitted by the bite of infected ticks.

• Infection results in skin lesions, headache, and fever, followed by meningoencephalitis and, eventually, arthritis.

• A bull’s-eye pattern rash with a red outer ring, called erythema migrans is a hallmark of this disease

Doxycyline

One of the preferred therapeutic options for lyme disease

Mycoplasma pneumoniae

• Walking pneumonia

• is a common cause of community-acquired pneumonia in young adults and in people who live in close connes, such as in military camps.

Macrolides or Doxycyline

Effective treatment for mycoplasma pneumoniae

Cholera

• is caused by Vibrio cholerae ingested in fecally contaminated food or water.

• The organism multiplies in the gastrointestinal tract, where it secretes an enterotoxin that produces diarrhea

Doxycycline

Treatment for cholera includes this, which reduces the number of intestinal vibrios, and fluid replacement

Chlamydia trachomatis

is the major cause of sexually transmitted disease in the United States. It causes nongonococcal urethritis, pelvic inammatory disease, and lymphogranuloma venereum.

Chlamydia psittaci

causes psittacosis, which usually takes the form of pneumonia. Other clinical forms include hepatitis, myocarditis, and coma

Doxycyline or azithromycin

Is used to treat chlamydial infections

Rocky mountain spotted fever

This disease, caused by Rickettsia rickettsii, is characterized by fever,chills, and aches in bones and joints.

Tetracyclines

Used in the treatment of rocky mountain spotted fever from which response is prompt if drug is started early in the disease process

Broad spectrum; effective against:

• Gram-positive bacteria

• Gram-negative bacteria

• Protozoa

• Spirochetes

• Mycobacteria

• Atypical species

What is the antibacterial spectrum of tetracyclines?

Broad spectrum; effective against:

• Gram-positive bacteria

  • Gram (+) cocci

    • S. aureus (include MRSA)

    • S. pneumoniae

  • Gram (+) bacilli

    • Bacillus anthracis

• Gram-negative bacteria

  • Gram (-) rods

    • Brucella species

    • Vibrio cholerae

    • Yersinia pestis

• Anaerobic organisms

  • C. perfringens

  • C. tetani

• Spirochetes

  • Borrelia burgdorferi

  • Leptospira interrogans

  • Treponema pallidum

• Mycoplasma

  • Mycoplasma pneumoniae

• Chlamydia

  • Chlamydia species

• Others

  • Rickettsia rickettsii

Typical therapeutic applications of tetracyclines

An efflux pump that expels the drug from the cell, preventing intracellular accumulation.

What is the most common resistance mechanism to tetracyclines?

• Enzymatic inactivation of the drug

• Production of proteins that block tetracycline binding to ribosomes

What are other bacterial mechanisms of resistance to tetracyclines?

No — resistance to one does not confer universal resistance to all tetracyclines

Does resistance to one tetracycline cause resistance to all tetracyclines?

At high concentrations, tetracyclines can interact with mitochondrial ribosomes, producing toxic effects because mitochondrial ribosomes resemble bacterial ribosomes

What is the most specific toxicity concern of tetracyclines

Adequately absorbed orally

How are tetracylcines absorbed

Decreased due to formation of nonabsorbable chelates

How is absorption of tetracyclines affected by dairy products and any substances containing divalent or trivalent cations (Mg²⁺, Al³⁺ antacids, Fe²⁺/Fe³⁺ supplements)

Doxycycline and minocycline are available as oral and IV preparations

Which tetracyclines are available in both oral and IV formulations?

They concentrate in bile, liver, kidney, gingival fluid, and skin.
They also bind to calcifying tissues (teeth and bones) and to calcium-rich tumors.

Where do tetracyclines concentrate in the body?

Minocycline and doxycycline

Which tetracyclines achieve therapeutic CSF levels?

Minocycline → reaches high levels in saliva and tears, useful for eradicating the meningococcal carrier state

Which tetracycline achieves high levels in saliva and tears, and what is it useful for?

Yes. All tetracyclines cross the placental barrier and accumulate in fetal bones and teeth.

Do tetracyclines cross the placenta?

• Tetracycline: eliminated unchanged in urine

• Doxycycline: eliminated primarily via bile → feces

• Minocycline: undergoes hepatic metabolism, partially eliminated via kidney
  None of these undergo hepatic metabolism except minocycline

How are tetracycline, doxycycline, and minocycline eliminated?

Doxycycline, because it is primarily eliminated in bile into feces, not reliant on renal clearance.

Which tetracycline is preferred in renal impairment, and why?

1. Gastric discomfort

2. Effects on calcified tissues

3. Hepatotoxicity

4. Phototoxicity

5. Vestibular dysfunction

6. Pseudotumor cerebri

Adverse effects of tetracyclines

Epigastric distress from mucosal irritation; may lead to noncompliance.

What GI effects are caused by tetracyclines

Minimized by:

• Taking with food (not dairy) or fluids

• Using capsules instead of tablets

How is esophagitis, one of the gastric adverse effects of tetracyclines, minimized

Tetracycline must be taken on an empty stomach.

How should tetracyclines be taken

They deposit in bone and primary dentition, causing:

• Tooth discoloration

• Enamel hypoplasia

• Temporary growth stunting
  → Leads to limited pediatric use.

How do tetracyclines affect calcifying tissues in children?

Those receiving high doses, especially:

• Pregnant women

• Patients with preexisting hepatic dysfunction

• Patients with renal impairment

What patients are at higher risk of hepatotoxicity from tetracyclines?

Severe sunburn may occur after UV exposure.
Most common with:

• Tetracycline

• Demeclocycline
  Patients must use sun protection.

Which tetracyclines most commonly cause phototoxicity, and what occurs?

Minocycline (most significant) and doxycycline.

Cause dizziness, vertigo, tinnitus due to accumulation in endolymph of the ear.

Which tetracyclines cause vestibular side effects and why?

A rare benign intracranial hypertension presenting with headache and blurred vision.
Usually reversible after stopping the drug, though permanent effects are uncertain

What is pseudotumor cerebri and how does tetracycline cause it?

• Pregnant women

• Breastfeeding women

• Children < 8 years old

Who should NOT receive tetracyclines?

Tigecycline is the first available member of the glycylcycline antimicrobial class, derived from minocycline.

What drug class does tigecycline belong to?

Tigecycline is indicated for:

• Complicated skin and soft tissue infections

• Complicated intra-abdominal infections

What are the approved clinical indications for tigecycline?

Tigecycline is bacteriostatic, acting by reversibly binding to the 30S ribosomal subunit and inhibiting protein synthesis.

What is the mechanism of action of tigecycline?

• MRSA

• Multidrug-resistant streptococci

• VRE (vancomycin-resistant enterococci)

• ESBL-producing gram-negative bacteria

• Acinetobacter baumannii

• Many anaerobes

Which organisms are covered by tigecycline?

Tigecycline is NOT active against:

• Morganella

• Proteus

• Providencia

• Pseudomonas

Which organisms are NOT susceptible to tigecycline?

Tigecycline

This was developed to overcome resistance in tetracycline-resistant organisms that use efflux pumps and ribosomal protection

Resistance is primarily due to overexpression of efflux pumps.

What is the main mechanism of resistance to tigecycline?

After IV infusion, tigecycline has a large volume of distribution and penetrates tissues well but has low plasma concentrations → therefore a poor option for bloodstream infections.

Describe tigecycline’s distribution and implication for bloodstream infections.

Primarily via biliary/fecal elimination.

How is tigecycline eliminated?

• No adjustment needed for renal impairment.

• Dose reduction recommended in severe hepatic dysfunction.

When are dose adjustments required with tigecycline?

Significant nausea and vomiting are strongly associated with tigecycline.

What is the most characteristic adverse effect of tigecycline?

Acute pancreatitis, including fatal cases.

What life-threatening adverse effect has been reported with tigecycline?

• Elevated liver enzymes

• Elevated serum creatinine

What lab abnormalities may occur with tigecycline?

• Photosensitivity

• Pseudotumor cerebri

• Discoloration of permanent teeth if used during development

• Fetal harm in pregnancy

Which tetracycline-class adverse effects also apply to tigecycline?

Tigecycline may decrease the clearance of warfarin → increases prothrombin time.
The INR must be monitored closely.

How does tigecycline interact with warfarin?

Aminoglycosides are bactericidal protein synthesis inhibitors used to treat serious infections caused by aerobic gram-negative bacilli.
Their utility is limited by serious toxicities.

What are aminoglycosides and what is their general clinical role?

Derived from Streptomyces spp. → suffix “-mycin”
Derived from Micromonospora spp. → suffix “-micin”

How are aminoglycoside names related to their microbial origin?

• Diffuse through porin channels in the outer membrane

• Transported across the inner membrane via an oxygen-dependent system (ineffective against anaerobes)

How do aminoglycosides enter bacterial cells?

They bind irreversibly to the 30S ribosomal subunit, causing:

• Interference with assembly of the ribosomal complex

• Misreading of mRNA, leading to defective proteins

What is the mechanism of action of aminoglycosides on the ribosome?

They are bactericidal, not bacteriostatic.

Why are aminoglycosides unique among protein synthesis inhibitors?

• Concentration-dependent killing → target Cmax = 8–10× MIC

• Postantibiotic effect (PAE) → prolonged suppression after levels drop below MIC
  These support extended-interval (once-daily) dosing, which reduces nephrotoxicity.

What pharmacodynamic properties define aminoglycoside efficacy?

Effective against aerobic gram-negative bacilli, including multidrug-resistant:

• Pseudomonas aeruginosa

• Klebsiella pneumoniae

• Enterobacter species

Which major pathogens are covered by aminoglycosides?

To achieve synergistic killing, particularly in Enterococcus faecalis and E. faecium endocarditis.

Why are aminoglycosides combined with β-lactams?

Tularemia

is acquired during rabbit hunting season by hunters skinning infected animals.

Pneumonic tularemia

results from infection by the respiratory route or by bacteremic seeding of lungs.

Gentamicin

This is effective in treating tularemia, a rare lymphoid disease

Pseudomonas aeruginosa

This gram (-) rod rarely attacks healthy individuals, but can cause infections in patients with specic risk factors (e.g., recent antibiotic exposure, prolonged hospitalization, bronchiectasis).

True or false

• Tobramycin

  • For UTI

• Tobramycin + antipseudomonal B-lactam

  • For pneumonia

Treatment for infections due to pseudomonas aeruginosa

• Gram (+) cocci

  • Enterococcus species

  • Streptococcus agalactiae

• Gram (-) rods

  • Actinobacter baumannii

  • Brucella species

  • Francisella tularensis

  • Klebsiella spieces

  • Pseudomonas aeruginosa

  • Yersinia pestis

Typical therapeutic applications of aminoglycosides

Ampicillin + gentamicin

Aminoglycoside treatment for infections caused by enterococcus species

Ampicillin + gentamicin

Aminoglycoside treatment for infections caused by streptococcus agalactiae

Gentamicin + doxycycline

Aminoglycoside treatment for infections caused by brucella species

Gentamicin

Aminoglycoside treatment for infections caused by francisella tularensis

Streptomycin

Aminoglycoside treatment for infections caused by yersinia pestis

• Efflux pumps

• Decreased uptake

• Enzymatic modification/inactivation via plasmid-encoded enzymes

What are the major resistance mechanisms to aminoglycosides?

No — modifying enzymes are drug-specific, so cross-resistance cannot be presumed.

Can cross-resistance among aminoglycosides be assumed?