unit 11: protein synthesis inhibitors

Protein Synthesis Inhibitors

* Selectively **inhibit bacterial protein synthesis**
* by binding to and interfering with ribosomes
* Basis for **selective toxicity** against microorganisms without causing major effects on mammalian cells

not identical

Protein synthesis in microorganisms is ___ to mammalian cells

70S

ribosomes in **bacteria**

80S

ribosomes in **mammalians**

Bacteriostatic

### Mechanism of Action

They do not kill the bacteria but instead **slow down the production of their proteins**

Bactericidal

### Mechanism of Action

They kill the bacteria

the **charged tRNA** unit carrying amino acid 6 __binds to the acceptor site on the 70S ribosome__

### Mechanism of Action

Step 1

**Transpeptidation**: **peptidyl tRNA** at the donor site, with amino acids 1 through 5, then __binds the growing amino acid chain to amino acid 6__

### Mechanism of Action

Step 2

**uncharged tRNA** left at the donor site is **released**

### Mechanism of Action

Step 3

**Translocation**:

**new 6-amino acid chain** with its tRNA __shifts to peptidyl site__

### Mechanism of Action

Step 4

**Chloramphenicol** & Macrolides

### Mechanism of Action

* inhibit the **transpeptidation**
* bind to the **50S** subunit

Macrolides, **telithromycin**, lincosamides

### Mechanism of Action

block the **translocation** of your peptidyl tRNA from the acceptor

Tetracyclines 

### Mechanism of Action

* bind to the **30S** subunit 
* prevent step 1

Streptogramins

### Mechanism of Action

constrict the **exit channel**

Linezolid

### Mechanism of Action

* block the **formation of the tRNA ribosomes and the mRNA complex**
* blocks the binding of the mRNA and tRNA to the ribosome
* difficult to form the peptide bonds

Active against both **aerobic and anaerobic gram-positive and gram negative** organisms

### Chloramphenicol

Antimicrobial Activity

**Plasmid-mediated** - chloramphenicol acetyltransferases

### Chloramphenicol

Resistance

Rickettsial infections

### Chloramphenicol*: Clinical Use*

typhus and Rocky Mountain spotted fever

Alternative to a β-lactam antibiotic

### Chloramphenicol*: Clinical Use*

treatment of **bacterial meningitis** occurring in patients who have **major hypersensitivity reactions to penicillin**

50-100 mg/kg/day divided every 6 hours

### Chloramphenicol*: Pharmacokinetics*

usual dosage

chloramphenicol succinate (prodrug)

### Chloramphenicol*: Pharmacokinetics*

IV formulation

* conjugation with glucuronic acid
* reduction to inactive aryl amines

### Chloramphenicol*: Pharmacokinetics*

Inactivated by

Active chloramphenicol + inactive degradation products

### Chloramphenicol*: Pharmacokinetics*

**Excretion**: urine

small amount of active drug

### Chloramphenicol*: Pharmacokinetics*

**Excretion**: bile and feces

Gray baby syndrome

### Chloramphenicol*: Toxicity*

Lacks effective glucuronic acid conjugation mechanism for the degradation and detoxification

gram-**positive** and gram-**negative**

### Tetracyclines

Antimicrobial Activity

* impaired influx or increased efflux
* ribosome protection
* enzymatic inactivation

### Tetracyclines

Resistance

* Mycoplasma pneumoniae
* Chlamydiae Rickettsiae
* Borrelia sp.
* Vibrios some spirochetes
* Anaplasma phagocytophilum
* Ehrlichia sp

### Tetracyclines

Primary Clinical Uses

* community-acquired pneumonia (CAP)
* syphilis
* Chronic bronchitis
* Leptospirosi
* Acne

### Tetracyclines

Secondary Clinical Uses

**Tetra**cycline

### Tetracyclines

**Selective Uses**: gastrointestinal ulcers caused by H. pylori

**Demeclo**cycline

### Tetracyclines

**Selective Uses**: ADH-­secreting tumors; inhibits the renal actions of antidiuretic hormone (ADH)

**Mino**cycline

### Tetracyclines

**Selective Uses**: meningococcal carrier state

**Doxy**cycline

### Tetracyclines: *Clinical Use*

* Lyme disease
* Malaria prophylaxis
* amoebiasis

**Tige**cycline

### Tetracyclines: *Clinical Use*

* MRSA strains
* VRE strains

60–70%

### Tetracyclines: *Pharmacokinetics*

Oral Absorption: **tetracycline and demeclocycline**

95-100%

### Tetracyclines: *Pharmacokinetics*

Oral Absorption: **doxycycline and minocycline**

**Tige**cycline and **Erava**cycline

### Tetracyclines: *Pharmacokinetics*

poorly absorbed orally and must be administered **intravenously**

breast milk

### Tetracyclines: *Pharmacokinetics*

Cross the **placental** barrier and excreted in ___

**Doxy**cycline and **tige**cycline: feces

### Tetracyclines: *Pharmacokinetics*

Excreted mainly in **bile and urine** except

**Tetra**cycline (oral) - 6-8 hours

### Tetracyclines: *Pharmacokinetics*

Short-acting

**Demeclo**cycline (oral) - 12 hours

### Tetracyclines: *Pharmacokinetics*

Intermediate-acting

**Doxy**cycline & **Mino**cycline (IV & Oral) - 16-18 hours

### Tetracyclines: *Pharmacokinetics*

Long-acting

**Tige**cycline and **Erava**cycline

### Tetracyclines: *Pharmacokinetics*

require **twice daily** dosing to maintain adequate serum concentrations

**Omada**cycline

### Tetracyclines: *Pharmacokinetics*

dosed once daily after an initial loading dose

Nausea, vomiting, diarrhea

### Tetracyclines*: Toxicity*

most common reasons for discontinuing tetracyclines

**Fanconi syndrome**: outdated

tetracyclines

### Tetracyclines*: Toxicity*

Renal toxicity

* **Tetra**cycline + diuretic
* **Tetra**cycline and **Mino**cycline

### Tetracyclines*: Toxicity*

Nephrotoxicity

**Demeclo**cycline

### Tetracyclines*: Toxicity*

Photosensitivity

**Doxy**cycline & **Mino**cycline

### Tetracyclines*: Toxicity*

Vestibular toxicity

Macrolides

* moderate spectrum
* macrocyclic lactone ring with attached sugars
* good oral bioavailability
* hepatic metabolism

**Ery**thromycin

### Macrolides

Prototype

**Clari**thromycin and **azi**thromycin

### Macrolides

**Semisynthetic derivatives** of erythromycin

**Inhibition of protein synthesis** occurs via binding to the 50S ribosomal RNA

### Macrolides

Mechanism of Action

torsades de pointes arrhythmia

### Macrolides

Macrolide antibiotics prolong the **electrocardiographic QT interval** due to an effect on __potassium channels__

2 hours (Oral & IV)

### Erythromycin

Half Life

1. **Reduced permeability** of the cell membrane or active efflux
2. Production (by Enterobacteriaceae) of **esterases** that hydrolyze macrolides
3. Modification of the ribosomal binding site (so-called **ribosomal protection**) by __chromosomal mutation or by a macrolideinducible or constitutive methylase__

### Erythromycin

Resistance

Food

### Erythromycin: *Pharmacokinetics*

interferes with absorption

bile

### Erythromycin: *Pharmacokinetics*

Excretion

polymorphonuclear leukocytes and macrophages

### Erythromycin: *Pharmacokinetics*

Taken up by ___

**penicillin substitute** in penicillin-allergic individuals with __infections caused by staphylococci and streptococci__

### Erythromycin

Clinical Use

**Clari**thromycin

### Macrolides

More active against **Mycobacterium avium complex**

6 hours (Oral)

### Clarithromycin

Half-life

**14-hydroxyclarithromycin** with antibacterial activity

### Clarithromycin: *Pharmacokinetics*

eliminated in the urine

patients with **creatinine clearances less than 30 mL/min**

### Clarithromycin: *Pharmacokinetics*

Dosage reduction

**Azi**thromycin

### Macrolides

* Spectrum of activity, mechanism of action, and clinical uses are **similar to those of clarithromycin**
* M avium complex, T gondii, H influenzae, Chlamydia sp

2-4 days (Oral & IV)

### Azithromycin

Half-life

Aluminum and magnesium antacids

### Azithromycin: *Pharmacokinetics*

do not alter bioavailability but delay absorption and reduce peak serum concentrations

Clindamycin

* **Chlorine-substituted derivative of** __**lincomycin**__ (Streptomyces lincolnensis)
* **Gram-negative aerobes** are __intrinsically resistant__

6-8 hours (Oral & IV)

### Clindamycin

Half-life

severe **anaerobic** infections

### Clindamycin*: Clinical Use*

Bacteroides, Fusobacterium, and Prevotella

**Backup drug** against gram-positive cocc

### Clindamycin*: Clinical Use*

Community-acquired strains of MRSA

Toxic shock syndrome

### Clindamycin*: Clinical Use*

with penicillin G

Penetrating wounds of the abdomen and gut

### Clindamycin*: Clinical Use*

combined with aminoglycoside or cephalosporin

**endocarditis** in valvular disease

### Clindamycin*: Clinical Use*

patients allergic to penicillin

**P. jiroveci pneumonia** in AIDS patients

### Clindamycin*: Clinical Use*

In combination with **primaquine alternative**

AIDS-related toxoplasmosis

### Clindamycin*: Clinical Use*

In combination with **pyrimethamine**

Quinupristin-Dalfopristin

### Streptogramins

Combination streptogramins

gram-**positive** cocci

### Streptogramins: *Quinupristin-Dalfopristin*

active against ___

0\.85 hours

### Streptogramins: *Quinupristin-Dalfopristin*

Quinupristin half-life

0\.7 hours

### Streptogramins: *Quinupristin-Dalfopristin*

Dalfopristin half-life

feces

### Streptogramins: *Quinupristin-Dalfopristin*

Excretion

Linezolid

### Oxazolidinones

* Active against gram-**positive** organisms
* Bacteriostatic but bactericidal against streptococci
* binds to **23S ribosomal RNA** of the 50S subunit

4-6 hours (Oral & IV)

### **Linezolid**

Half-life

thrombocytopenia

### **Linezolid**

most common manifestation

Tedizolid

### Oxazolidinones

* Active moiety of the prodrug tedizolid phosphate
* High potency against gram-positive bacteria

Plasma concentrations

### Tedizolid: *Pharmacokinetics*

**good indicator for tissue concentrations** as it penetrates well into muscle, adipose, and pulmonary tissues

12 hours

### Tedizolid

Half-life

Pleuromutilins

discovered in the 1950s but previously it was only used in **veterinary** **medicine**.

Lefamulin

### Pleuromutilins

* Approved only for the treatment of adult patients with **community acquired pneumonia**
* lower respiratory tract infections
* in vitro activity against most a**erobic gram-positive organisms**

hepatic metabolism (CYP3A4)

### Lefamulin

Excretion

8 hours, 2x daily

### Lefamulin

Half-life