Antibiotics: Inhibitors of Protein Synthesis

Notes on Tetracycline, Chloramphenicol, Aminoglycosides, Macrolides & Clindamycin
“Antimicrobial” is a general term that refers to a group of drugs that includes antibiotics, antifungals, antiprotozoals, and antivirals. An antibiotic is a drug used to treat infections caused by bacteria and other microorganisms. Originally, an antibiotic was a substance produced by one microorganism that selectively inhibits the growth of another.
Understanding biosynthesis of proteins (translation process):
http://tube.medchrome.com/2010/10/biosynthesis-of-protein-translation.html
Different steps in protein synthesis are susceptible to inhibition by antibiotics of different groups.
TETRACYCLINES
Broad spectrum and Bacteriostatic Antimicrobial Agents (AMAs)
Features | TetracyclineOxytetracycline | Demelocycline | DoxycyclineMinocycline |
Potency | Low | Intermediate | High |
Intestinal absorption | Moderate | Moderate | Complete (no food interference) |
Plasma half life | Relatively low | Higher than tetracycline and oxytetracycline | Highest |
Alteration of intestinal flora | Marked | Moderate | Least |
Diarrhea | High | Intermediate | Low |
Phototoxicity | Low | Highest | High |
Specific toxicity | Less tooth decoloration | More phototoxic, diabetes insipidus | Low renal and vestibula toxicities |
Mechanism of Action (MOA):
Tetracycline – – binds – -> 30s ribisomes – -X – -> attachment of aminoacyl-t-RNA to mRNA-ribosome complex – – -> inhibition of peptide synthesis
Pharmacokinetics:
- Concentrated in liver, spleen, bone and teeth
- Secreted in milk
- Oral capsule: should be taken ½ hour before or 2 hours after the food
Adverse Effects:
- Gastrointestinal upset : gastric pain, nausea, vomiting diarrhea due to
- Direct mucosal irritant action of substance
- Damage to natural gut flora (common A/E of broad spectrum antibiotics) and superinfection by pathogenic organisms including candida
- Accumulation in teeth and bone (chelation of Calcium):
- irreversible yellow-brownish discoloration of teeth
- reversible suppression of bone growth
- teratogenecity
- Phototoxicity
- Hepatic damage: fatty infiltration and jaundice
- Renal damage: Renal failure, Fancony syndrome
- Esophageal ulceration and thrombophlebitis
- Vestibular toxicity: ataxia, vertigo and nystagmus
- Hypersensitivity
- Diabetes insipidus: with Demelocycline
Uses or Indications:
- Empirical therapy in serious and mixed infections
- 1st choice drugs in:
- Veneral diseases: urethritis, granuloma inguinale
- Atypical pneumonia due to Mycoplasma pneumonia
- Cholera
- Brucellosis
- Plague: both bubonic and pneumonic plague
- Relpasing fever
- Rickettsial infections: typhus, Q fever
- 2nd choice drugs in:
- Tetanus, anthrax, actinomycosis, gonorrhea, syphilis, leptospirosis, pneumonia due to Chlamydia pneumonia, chancroid, tularemia
- Others:
- UTI
- Amoebiasis
- Falciparum malaria
- Acne vulgaris
- Chronic obstructive lung disease
Point to Remember:
Concurrent ingestion of antacids and milk would be inappropriate because tetracycline form insoluble complexes with plurivalent cations (eg. Ca2+, Mg2+, Al3+,etc.) resulting in their inactication. i.e. absorbability, antibacterial activity and local irritant action are abolished.
AMINOGLYCOSIDES
- Bactericidal Antimicrobial Agents (AMA)
- Spectrum: Mainly gram negative organisms
- Mycins designates origin from Streptomyces species and Micin from Micromonospra species
Classification:
Systemic:
- Streptomycin
- Gentamycin
- Kanamycin
- Tobramycin
- Amikacin
Topical:
- Neomycin
- Framycetin
Mechanism of Action (MOA):
- Bind to several sites at 30S and 50S subunits as well as 30S-50S interface à Freeze initiation, interfere with polysome formation
- Induce binding of wrong t-RNA-AA complexes resulting in false proteins
Shared toxicity:
A. Ototoxicity (in part irreversible):
- Cochlear damage (Organ of corti): tinnitus and hearing loss
- Vestibular damage (hair cells) : headache, nausea, vomiting, dizziness, nystagmus, vertigo, ataxia
B. Nephrotoxicity (mostly reversible):
In the kidney, they enter the cells of the proximal tubules via an uptake system for oligopeptides. Tubular cells are susceptible to damage
- Loss of urinary concentrating power
- Decreased gfr, nitrogen retention, albuminuria
- Decreased clearance of antibiotic à increased blood levels à increased ototoxicity
C. Neuromusuclar blockade:
- Reduction in Acetylcholine (Ach) release from motor nerve endings
- Antagonizes Calcium
- Increases myasthenic weakness
Systemic Aminoglycosides:
Streptomycin vs Gentamycin:
Features | Streptomycin | Gentamycin |
Potency | Relatively less | Relatively more |
Spectrum | Narrow | Broader |
Nephrotoxicity | Lowest among aminoglycosides | Relatively more |
Action against M.tuberculosis, S.Pyrogens, S. pneumoniae | Present | Absent |
Uses | TB, SABE (Subacute Bacterial Endocarditis), Plague, Tularemia | RTI (Respiratory Tract Infection), gram negative meningitis, SABE, UTI, pneumonia, septicemia |
Topical Aminoglycosides:
Neomycin
- Wide-spectrum aminoglycosides
- Pseudomonsa and Streptococcus pyogens are insensitive
Uses or Indications:
Topically:
- infected wound
- ulcers
- burn
- external ear infection
- conjunctivitis
Orally:
- Preparation of bowel before surgery
- Hepatic coma
Adverse Effects (A/E):
- Rashes
- Malabsorption syndrome with diarrhea and steatorrhoea
- Superinfection by candida
- Nephrotoxicity and Ototoxicity
- Neuromuscular blockade à apnoea
CHLORAMPHENICOL
- Broad spectrum and Bacteriostatic Antibiotic
- Crosses placenta, Blood brain barrier and is secreted in bile and milk
Mechanism of Action (MOA):
- Attaches to 50S ribosome
- Inhibits peptide synthetase or peptidyl transferase (enzyme that links the AAs of two t-RNA-AA complexes)
Adverse Effects:
- Bone marrow depression: leading to aplastic anemia, agranulocytosis, thrombocytopenia
- Hypersensitivity
- Nausea, vomiting, diarrhea, pain on injection
- Superinfections : < than tetracyclines
- Gray baby syndrome:
- Occurs due to inability of the newborn to adequately metabolize and excrete chloramphenicol
- Effects: Stop feeding, vomiting, hypotonia, hypothermia, irregular respiration, gray cyanosis, CV collapse, death
Uses or Indications:
- Typhoid
- Pyogenic meningitis
- Anaerobic infections
- Intraocular infections
- Brucellosis and reickettsial infection
- Whooping cough
- UTI
Point to Remember:
Chloramphenicol despite of crossing diffusion barriers readily, it is rarely indicated (e.g., in CNS infections) because of the danger of bone marrow supression. 2 types of bone marrow depression can occur:
- Dose-dependent, toxic, reversible form manifested during therapy
- Frequently fatal form that may occur after a latency of weeks and is not dose dependent.
MACROLIDES (Romycins)
Classification:
- Erythromycin
- Newer Macrolides:
- Roxithromycin
- Clarithromycin
- Azithromycin
- Sipramycin
Erythromycin:
Bacteriostatic (mainly directed towards gram positive organisms) but cidal at higher concentration
Mechanism of Action (MOA):
Combines with 50s ribosome and interferes with translocation process – – -> premature termination of peptide chain. If you need research peptides for your research project, make sure to get it from legit sites online.
Pharmacokinetics:
- Acid labile
- Incomplete absorption, food interference
Adverse Effects:
- Epigastric pain, diarrhea
- Reversible hearing impairment
- Hypersensitivity: Rashes, fever, hepatitis with cholestatic jaundice
Uses or Indications:
Alternative to penicillin (in case of penicillin allergy or resistance)
- DPT
- Diptheria
- Whooping Cough (Pertusis)
- Tetanus
- STDs:
- Syphilis
- Chancroid
- SABE
- Rheumatic fever
- Chlamyda trachomatis
Newer Macrolides: overcomes –
- Narrow spectrum
- Gastric intolerance, gastric lability
- Low oral bioavailability
- Poor tissue penetration
- Short plasma half life
e.g. Roxithromycin, Clarithromycin, Azithromycin
LINCOSAMIDES
Clindamycin is a semisynthetic derivative of Lincomycin.
Clindamycin:
- Inhibits most gram positive cocci
- Mechanism of action (MOA): similar to that of erythromycin
Adverse effects:
- Rashes, urticaria, abdominal pain
- Diarrhea
- Pseudomembranous enterocolitis due to C.difficile superinfection
Uses or Indications:
- Bone and joint infection: due to anaerobic Streptococcus and Clostridium perfringes
- Prophylaxis of endocarditis in Penicillin allergic patients
- Toxoplasmosis and Pneumocystis Jiroveci
Birds eye view:
2 Comments
Although this article speaks of mechanisms of antibiotics, it does not do justice to the topic. There are several mechanisms of action for different classes of antibiotics. PharmaXChange.info has a wide variety of animations for the mechanisms of actions of different antibiotics. I would definitely recommend readers of this article to check out that page as well.
Hello Akul,
This article is particularly talking about the antibiotics that acts by inhibiting protein synthesis in various steps. It is true that the antibiotics as a whole cannot be limited only to this specific mechanism of action.
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