Pharmacology 2: Protein Synthesis Inhibitors

Pharmacology 2

•  Covered topics include Chloramphenicol, Tetracyclines, Macrolides, Clindamycin, Streptogramins, and Linezolid.

Introduction

• Drugs inhibit bacterial protein synthesis by binding to and interfering with ribosomes.
• Most are bacteriostatic, while a few are bactericidal against specific organisms.
• Tetracycline and macrolide resistance is common.

Cell Wall Synthesis

• Includes Beta Lactams, Penicillins, Cephalosporins, Carbapenems, Monobactams, Vancomycin, and Bacitracin.

Nucleic Acid Synthesis

• Includes Folate synthesis (Sulfonamides, Trimethoprim), DNA Gyrase (Quinolones), and RNA Polymerase (Rifampin).

Cell Membrane

• Includes Polymyxins

Protein Synthesis

• Includes 50S subunit and 30S subunit inhibitors (Tetracyclines, Aminoglycosides, Macrolides, Clindamycin, Linezolid, Chloramphenicol, Streptogramins).

Inhibitors of Microbial Protein Synthesis

• Drugs vary in chemical structures and antimicrobial activity spectra.
• Categorized as broad spectrum, moderate spectrum, and narrow spectrum based on their effects.

Mechanisms of Action

• Most antibiotics in the chapter are bacteriostatic inhibitors of protein synthesis that act on the ribosomal level.
• Binding sites are primarily located on the 50S ribosomal subunit.
• Chloramphenicol inhibits transpeptidation by blocking the aminoacyl moiety binding to the mRNA complex.

Chloramphenicol

• Simple, distinctive structure—no other similar antimicrobials have been discovered.
• Effective orally and parenterally with placental and blood-brain barrier penetration.
• Undergoes enterohepatic cycling; a portion is excreted unchanged in the urine.
• Primarily inactivated by hepatic glucuronosyltransferase.
• Bacteriostatic, with some bactericidal activity against specific organisms (Haemophilus influenzae, Neisseria meningitidis, Bacteroides).
• Ineffective against Chlamydia species.
• Resistance is plasmid-mediated, mediated by acetyltransferases.
• Limited clinical uses due to toxicity.
• Backup drug for severe Salmonella, pneumococcal, and meningococcal infections (in beta-lactam-sensitive cases).
• Used sometimes in rickettsial diseases and infections caused by anaerobes (e.g., Bacteroides fragilis).
• Commonly used as a topical antimicrobial agent.
• Potential toxicities include gastrointestinal disturbances (especially candidiasis), bone marrow suppression (decrease in circulating erythrocytes), and gray baby syndrome (in infants, characterized by decreased red blood cells, cyanosis, and cardiovascular collapse).
• Drug interactions with hepatic drug metabolizing enzymes exist, increasing elimination half-lives of other drugs (e.g., phenytoin, tolbutamide, and warfarin).

Tetracyclines

•  Crystalline, amphoteric substances; low solubility.
• Available as hydrochlorides (more soluble).
• Tetracycline solutions acidic and relatively stable.
• Chelate divalent metal ions, interfering with absorption and activity.
• Tigecycline is a glycylcycline and a semisynthetic derivative of minocycline.
• Broad-spectrum bacteriostatic antibiotics with only minor differences in their activities against specific organisms.
• Oral absorption may be impaired by foods and multivalent cations (calcium, iron, aluminum).
• Penetrate the placental barrier.
• Undergo enterohepatic cycling; eliminated primarily in feces and the urine; doxycycline and minocycline have longer half-lives compared to others.
• Tigecycline is IV use-only; half-life of 30-36 hrs.
• Resistance mechanisms include efflux pumps and ribosomal protection proteins interfering with tetracycline binding.
• Resistance to tigecycline is rare; resistance is primarily associated with efflux pumps in Proteus and Pseudomonas.
• Clinical uses include treatment of Mycoplasma pneumoniae infections, chlamydiae, rickettsiae, vibrios, and some spirochetes (most commonly).
• Alternate treatment for community-acquired pneumonia.
• Used in treatment of secondary problems such as syphilis, respiratory infections, prevention of infection in chronic bronchitis, treatment of leptospirosis, and treatment of acne.
• Selective clinical uses for helicobacter pylori infections, Lyme disease, and meningococcal carrier state.
• Tigecycline is a clinical use with unique features, providing a broad spectrum active against many resistant organisms. Intravenous use only.
• Risk of gastrointestinal disturbances, teeth and bony structure effects, and hepatic toxicity.

Macrolides

• Large cyclic lactone ring structures with attached sugars.
• Drugs have good oral bioavailability, but absorption of azithromycin is often hindered by food.
• Distribute to most body tissues.
• Azithromycin elimination is slow, with a half-life of 2-4 days
• Rapid elimination (2 or 6 hours).
• Similar antibacterial activity, with extended activity against Mycobacterium avium complex and Toxoplasma species.
• Used in the treatment of urogenital infections (C trachomatis), community-acquired pneumonia, as a prophylactic or treatment of AIDS-related toxoplasmosis, or as a component of ulcer treatment (H. pylori) regimens.
• Fidaxomicin is a narrow-spectrum macrolide, inhibiting protein synthesis and targeting gram-positive aerobes and anaerobes.
• Effective in C. difficile colitis.
• Side effects include GI irritation (especially with erythromycin), skin rashes, and eosinophilia.
• Potential hepatotoxicity is rare (primarily with erythromycin estolate, especially in pregnant patients).

Telithromycin

• Ketolide structurally related to macrolides.
• Similar mechanism of action and activity spectrum to erythromycin.
• Treats community-acquired pneumonia.
• Hepatic dysfunction and prolonged QT interval are possible side effects.

Clindamycin

• Inhibits bacterial protein synthesis via a unique mechanism, though non-chemically related to macrolides.
• Resistance mechanisms include methylation of the 50S ribosomal subunit and enzymatic inactivation.
• Gram-negative aerobes are inherently resistant.
• Good tissue penetration after oral absorption.
• Primarily eliminated by biliary and renal excretion (both intact drug and metabolites).
• Used to treat severe infections (anerobic bacteria).
• Also active against gram-positive cocci (some community-acquired strains) with methicillin-resistant S aureus prophylaxis for endocarditis in patients with penicillin allergies).
• Active against Pneumocystis jirovecii and used with pyrimethamine for AIDS-related toxoplasmosis.
• Adverse effects: gastrointestinal irritation, skin rashes, neutropenia, hepatic dysfunction, and superinfections (such as Clostridium difficile-related colitis).

Streptogramins

• Combination of quinupristin-dalfopristin, two streptogramins.
• Bactericidal with longer antibacterial activity.
• Treats penicillin-resistant pneumococci, methicillin-resistant MRSA and vancomycin-resistant staphylococci, and E faecium.
• Administered intravenously to avoid pain and arthralgia-myalgia syndrome.
• Potent inhibitors of CYP3A4; increase plasma levels of other common drugs (astemizole, cisapride, cyclosporine, diazepam, other non-nucleoside reverse transcriptase inhibitors, and warfarin).

Linezolid

• First oxazolidinone antibiotic.
• Active against drug-resistant gram-positive cocci (including MRSA, PRSP, and VRE).
• Also active against L. monocytogenes and corynebacteria.
• Binds to a unique site on the 23S ribosomal RNA of the 50S ribosomal subunit; minimal cross-resistance with other protein synthesis inhibitors.
• Oral and parenteral formulations; hepatic metabolism.
• Elimination half-life is 4-6 hours.
• Side effects: thrombocytopenia, neutropenia (particularly in immunosuppressed patients); possible serotonin syndrome (with SSRIs).