MECHANISMS OF ACTION OF PROTEIN SYNTHESIS INHIBITORS UNVEILED

Introduction

Protein synthesis inhibitors are antibiotics that prevent bacteria from producing essential proteins needed for growth and survival. These antibiotics work by binding to the 30S ribosomal subunit, which is responsible for protein synthesis. The most common mechanism of action of protein synthesis inhibitors is to bind to the peptidyl transferase center of the 30S ribosomal subunit, thereby inhibiting the translocation of amino acids during protein synthesis.

There are several mechanisms of bacterial resistance to protein synthesis inhibitors, including:

1. Modification of the target site: Bacteria can modify the target site of protein synthesis inhibitors, such as the 30S ribosomal subunit, making it less accessible to the antibiotic.

2. Overexpression of efflux pumps: Bacteria can overexpress efflux pumps, which can expel the antibiotic from the cell, reducing its effectiveness.

3. Enzymatic degradation: Bacteria can produce enzymes that can degrade the antibiotic, rendering it ineffective.

4. Alteration of the antibiotic’s chemical structure: Bacteria can modify the chemical structure of the antibiotic, making it less effective or unable to bind to the target site.

5. Target modification: Bacteria can modify the target protein itself, making it less susceptible to inhibition by the antibiotic.

It is important to note that the development of bacterial resistance to protein synthesis inhibitors is a major concern, and the overuse and misuse of these antibiotics can accelerate the emergence of resistant strains. Therefore, it is crucial to use these antibiotics judiciously and only when necessary to minimize the risk of resistance development.

 

Therapeutic indications for each class of antibiotics

Antibiotics are a class of drugs used to treat bacterial infections. They work by either killing bacteria or inhibiting their growth. There are several classes of antibiotics, each with its own mechanism of action and spectrum of activity. The therapeutic indications for each class of antibiotics are as follows:

1. Penicillins: Penicillins are one of the oldest and most widely used classes of antibiotics. They work by inhibiting the synthesis of bacterial cell walls, leading to cell lysis and death. Penicillins are commonly used to treat a variety of infections caused by susceptible bacteria, including respiratory tract infections (such as pneumonia and bronchitis), skin and soft tissue infections, urinary tract infections, and certain sexually transmitted diseases. Some examples of penicillins include amoxicillin, ampicillin, and penicillin G.

2. Cephalosporins: Cephalosporins are structurally related to penicillins and have a similar mechanism of action. They also inhibit bacterial cell wall synthesis but have a broader spectrum of activity compared to penicillins. Cephalosporins are commonly used to treat respiratory tract infections, skin and soft tissue infections, urinary tract infections, and certain types of meningitis. They are also used as surgical prophylaxis to prevent postoperative infections. Examples of cephalosporins include ceftriaxone, cephalexin, and ceftazidime.

3. Macrolides: Macrolides work by inhibiting bacterial protein synthesis. They bind to the 50S subunit of the bacterial ribosome, preventing the formation of new proteins necessary for bacterial growth and survival. Macrolides are commonly used to treat respiratory tract infections (such as community-acquired pneumonia), skin and soft tissue infections, and certain sexually transmitted diseases. They are also effective against atypical pathogens like Mycoplasma pneumoniae and Legionella pneumophila. Examples of macrolides include azithromycin, clarithromycin, and erythromycin.

4. Tetracyclines: Tetracyclines inhibit bacterial protein synthesis by binding to the 30S subunit of the bacterial ribosome. They are broad-spectrum antibiotics effective against a wide range of bacteria, including both gram-positive and gram-negative organisms. Tetracyclines are commonly used to treat respiratory tract infections, skin and soft tissue infections, urinary tract infections, and certain sexually transmitted diseases. They are also used in the treatment of acne and certain tick-borne illnesses such as Lyme disease. Examples of tetracyclines include doxycycline, minocycline, and tetracycline.

5. Fluoroquinolones: Fluoroquinolones work by inhibiting bacterial DNA synthesis by targeting DNA gyrase or topoisomerase IV enzymes. They have a broad spectrum of activity against both gram-positive and gram-negative bacteria. Fluoroquinolones are commonly used to treat respiratory tract infections (including community-acquired pneumonia), urinary tract infections, skin and soft tissue infections, and certain sexually transmitted diseases. They are also used in the treatment of complicated intra-abdominal infections and certain types of bone and joint infections. Examples of fluoroquinolones include ciprofloxacin, levofloxacin, and moxifloxacin.

6. Aminoglycosides: Aminoglycosides inhibit bacterial protein synthesis by binding to the 30S subunit of the bacterial ribosome. They have a narrow spectrum of activity primarily against gram-negative bacteria but can also be effective against some gram-positive organisms when used in combination with other antibiotics. Aminoglycosides are commonly used to treat severe infections caused by multidrug-resistant gram-negative bacteria, such as Pseudomonas aeruginosa and Acinetobacter baumannii. They are also used in the treatment of certain types of tuberculosis and endocarditis. Examples of aminoglycosides include gentamicin, amikacin, and tobramycin.

7. Sulfonamides: Sulfonamides inhibit bacterial folic acid synthesis by acting as competitive inhibitors of the enzyme dihydropteroate synthase. They have a broad spectrum of activity against both gram-positive and gram-negative bacteria. Sulfonamides are commonly used to treat urinary tract infections, respiratory tract infections (such as bronchitis), and certain types of skin and soft tissue infections. They are also used in the treatment of certain protozoal infections, such as toxoplasmosis and Pneumocystis jirovecii pneumonia. Examples of sulfonamides include sulfamethoxazole, sulfadiazine, and trimethoprim-sulfamethoxazole (TMP-SMX).

8. Glycopeptides: Glycopeptides inhibit bacterial cell wall synthesis by binding to the D-alanyl-D-alanine terminus of peptidoglycan precursors, preventing their incorporation into the growing cell wall. They are primarily active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Glycopeptides are commonly used to treat serious infections caused by gram-positive organisms, such as bloodstream infections, endocarditis, and bone and joint infections. Vancomycin is the most commonly used glycopeptide antibiotic.

9. Carbapenems: Carbapenems inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs). They have a broad spectrum of activity against both gram-positive and gram-negative bacteria, including many multidrug-resistant organisms. Carbapenems are commonly used to treat severe infections, such as complicated intra-abdominal infections, complicated urinary tract infections, and hospital-acquired pneumonia. Examples of carbapenems include imipenem-cilastatin, meropenem, and doripenem.

10. Oxazolidinones: Oxazolidinones inhibit bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome. They are primarily active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). Oxazolidinones are commonly used to treat skin and soft tissue infections caused by MRSA and certain types of pneumonia caused by VRE. Linezolid is the most commonly used oxazolidinone antibiotic.

It is important to note that the therapeutic indications mentioned above are general guidelines, and the choice of antibiotic should be based on the specific characteristics of the infection, including the causative organism, its susceptibility pattern, and patient-specific factors such as allergies and renal function.

 

Various toxicities associated with each class of antibiotics

1) Penicillins:

• Allergic reactions: Penicillins are known to cause allergic reactions in some individuals, ranging from mild skin rashes to severe anaphylaxis.
• Gastrointestinal effects: Common side effects include nausea, vomiting, diarrhea, and abdominal pain.
• Neurotoxicity: High doses of penicillins can lead to neurotoxicity, causing symptoms such as confusion, seizures, and hallucinations.
• Hematologic effects: Some penicillins can cause a decrease in the number of blood cells, leading to anemia, leukopenia, or thrombocytopenia.
• Renal toxicity: Certain penicillins can cause kidney damage or impair renal function.

 

2) Cephalosporins:

• Allergic reactions: Cephalosporins can also trigger allergic reactions, including rashes, hives, and anaphylaxis.
• Gastrointestinal effects: Similar to penicillins, cephalosporins may cause gastrointestinal disturbances like nausea, vomiting, diarrhea, and abdominal pain.
• Hematologic effects: Some cephalosporins have been associated with blood disorders such as eosinophilia, leukopenia, or thrombocytopenia.
• Nephrotoxicity: Certain cephalosporins can lead to kidney damage or impaired renal function.
• Neurotoxicity: High doses of cephalosporins may result in neurotoxicity symptoms like confusion or seizures.

 

3) Tetracyclines:

• Gastrointestinal effects: Tetracyclines are known to cause gastrointestinal disturbances such as nausea, vomiting, diarrhea, and abdominal pain.
• Photosensitivity: Tetracyclines can make the skin more sensitive to sunlight and increase the risk of sunburns or rashes when exposed to UV radiation.
• Hepatotoxicity: Rarely, tetracyclines can cause liver damage or impair liver function.
• Renal toxicity: High doses of tetracyclines may lead to kidney damage or impaired renal function.
• Dental discoloration: Tetracyclines can cause permanent discoloration of developing teeth in children.

 

4) Macrolides:

• Gastrointestinal effects: Macrolides are known to cause gastrointestinal disturbances such as nausea, vomiting, diarrhea, and abdominal pain.
• Hepatotoxicity: Some macrolides have been associated with liver damage or impaired liver function.
• QT interval prolongation: Certain macrolides can prolong the QT interval on an electrocardiogram, potentially leading to a life-threatening arrhythmia called torsades de pointes.
• Allergic reactions: Although rare, macrolides can trigger allergic reactions ranging from mild skin rashes to severe anaphylaxis.
• Ototoxicity: High doses of macrolides may result in temporary or permanent hearing loss or tinnitus.

 

5) Aminoglycosides:

• Nephrotoxicity: Aminoglycosides are known to cause kidney damage or impaired renal function, especially when used for prolonged periods or at high doses.
• Ototoxicity: A significant side effect of aminoglycosides is ototoxicity, which can lead to irreversible hearing loss or balance problems.
• Neuromuscular blockade: Aminoglycosides can interfere with neuromuscular transmission, resulting in muscle weakness or paralysis.

 

6) Fluoroquinolones:

• Tendinopathy and tendon rupture: Fluoroquinolones have been associated with an increased risk of tendinopathy (inflammation) and tendon rupture, particularly in the Achilles tendon.
• QT interval prolongation: Some fluoroquinolones can prolong the QT interval on an electrocardiogram, potentially leading to a life-threatening arrhythmia called torsades de pointes.
• Central nervous system effects: Fluoroquinolones may cause central nervous system side effects such as dizziness, confusion, hallucinations, or seizures.
• Photosensitivity: Similar to tetracyclines, fluoroquinolones can increase the skin’s sensitivity to sunlight and raise the risk of sunburns or rashes when exposed to UV radiation.
• Gastrointestinal effects: Common side effects include nausea, vomiting, diarrhea, and abdominal pain.

 

Drug interaction of tetracyclines and antacid

Tetracyclines are a group of antibiotics commonly used to treat various bacterial infections. They work by inhibiting the growth and replication of bacteria.

Antacids, on the other hand, are medications used to neutralize stomach acid and provide relief from conditions such as heartburn and acid reflux.

When tetracyclines and antacids are taken together, they can interact and potentially affect the absorption and effectiveness of the antibiotic. This interaction occurs due to the chemical properties of both medications.

Antacids contain compounds such as aluminum, calcium, magnesium, or sodium bicarbonate, which act as bases to neutralize stomach acid. These compounds can form complexes with tetracyclines in the gastrointestinal tract, leading to the formation of insoluble chelates. Chelation refers to the binding of a metal ion (in this case, tetracycline) by another molecule (in this case, an antacid compound) to form a stable complex.

The formation of these insoluble chelates reduces the absorption of tetracyclines from the gastrointestinal tract into the bloodstream. As a result, less of the antibiotic reaches its target site in the body, reducing its effectiveness in treating bacterial infections.

It is important to note that not all antacids have equal effects on tetracycline absorption. Aluminum and magnesium-containing antacids have been found to have more significant interactions compared to calcium-based antacids. Additionally, certain antacid formulations, such as those containing carbonate or bicarbonate salts, are more likely to cause chelation with tetracyclines than others.

To minimize the drug interaction between tetracyclines and antacids, it is recommended to separate their administration by at least two hours. This time interval allows for sufficient absorption of tetracyclines before taking an antacid, reducing the likelihood of chelation and subsequent decreased antibiotic efficacy.

It is worth mentioning that other medications and substances can also interact with tetracyclines, affecting their absorption or effectiveness. For example, dairy products, iron supplements, and certain minerals can form chelates with tetracyclines, leading to reduced absorption. Therefore, it is crucial to consult a healthcare professional or read the medication’s label for specific instructions on drug interactions and administration guidelines.

In summary, the interaction between tetracyclines and antacids occurs due to the formation of insoluble chelates in the gastrointestinal tract. This interaction reduces the absorption of tetracyclines, potentially compromising their effectiveness in treating bacterial infections. Separating the administration of these medications by at least two hours can help minimize this interaction.

 

Adverse effects and contraindications of Tetracycline, Chloramphenicol, and Aminoglycosides

Tetracycline, Chloramphenicol, and Aminoglycosides are antibiotics that are commonly used to treat bacterial infections. However, like all medications, they can have adverse effects, especially when used improperly or in certain populations.

1) Adverse effects of Tetracycline:

• Gastritis (inflammation of the stomach).
• Esophageal ulcers.
• Black hairy tongue (a condition where the tongue becomes darkened and hair-like).
• Diarrhea.
• Nausea and vomiting.
• Increased risk of sun sensitivity.

Contraindications in children:

Tetracycline is not recommended for children under the age of 8, as it can cause tooth discoloration and affect bone growth.

 

2) Adverse effects of Chloramphenicol:

• Allergic reactions, including anaphylaxis.
• Gastrointestinal disturbances, such as nausea, vomiting, and diarrhea.
• Increased risk of sun sensitivity.
• Blood dyscrasias, such as aplastic anemia and leukopenia.

Contraindications in children:

Chloramphenicol is not recommended for children under the age of 12, as it can cause bone marrow suppression.

 

3) Adverse effects of Aminoglycosides:

• Ototoxicity (damage to the inner ear).
• Nephrotoxicity (damage to the kidneys).
• Allergic reactions, including anaphylaxis.
• Gastrointestinal disturbances, such as nausea, vomiting, and diarrhea.

Contraindications in pregnant women:

Aminoglycosides are category B drugs during pregnancy, which means that animal studies have shown adverse effects on the fetus, but there are no adequate and well-controlled studies in pregnant women. As a precaution, these drugs should be used during pregnancy only if the potential benefit justifies the potential risk.

It’s important to note that these adverse effects and contraindications can vary depending on the specific medication and the individual patient. It’s important to consult with a healthcare professional before taking any medication, especially if you have a pre-existing condition or are pregnant or breastfeeding.