Glycopeptides and Their Mechanism of Action

Glycopeptides

• Vancomycin and teicoplanin are large molecules that inhibit cell wall synthesis at the second and third stages
• They directly bind to the D-alanyl-D-alanine portion of the pentapeptide, leading to blocking transglycosylation and transpeptidation
• This prevents peptidoglycan cross-linking, similar to the effect of β-lactams
• Glycopeptides are not active against gram-negative bacteria due to their large size, which prevents them from penetrating the outer membrane
• They are bactericidal and primarily effective against gram-positive bacteria, particularly against multi-resistant strains such as MRSA/MRSE
• They are used for serious infections in individuals with penicillins allergies
• They are not active orally, but are used to treat Clostridium difficile infections of the bowel
• Lipoglycopeptides, including Telavancin (short-acting), Dalbavancin, and Oritavancin (long-acting) are derivatives of glycopeptides with long half-lives (150-250 h)
• These are prescribed for acute bacterial skin and soft tissue infections, with doses ranging from twice per week to once a week

Miscellaneous Cell Wall Inhibitors

• Fosfomycin:
  • Inhibits the first step in peptidoglycan synthesis, preventing NAM formation from NAG
  • Limited use for lower urinary tract infections (cystitis)
  • High incidence of bacterial resistance
• Cycloserine:
  • Affects peptidoglycan synthesis by inhibiting enzymes responsible for D-alanine formation from L-alanine in the bacterial cytoplasm
  • Prevents the formation of D-alanyl-D-alanine dipeptide, a crucial component of peptidoglycan
  • Used as a second-line drug in tuberculosis treatment, only when first-line drugs are ineffective due to its neurological side effects
• Bacitracin:
  • Prevents the dephosphorylation of bactoprenol, a phospholipid responsible for transporting peptidoglycan subunits across the cell membrane
  • This blocks the regeneration of the lipid carrier and inhibits cell wall synthesis
  • Useful for treating superficial skin infections, but systemic use is limited due to kidney damage
• Isoniazid:
  • Interferes with the synthesis of mycolic acid, a component of the cell wall of acid-fast organisms (Mycobacterium tuberculosis)
  • Effective in treating infections with Mycobacterium tuberculosis

Antibacterial Drugs Affecting the Bacterial Cell Membrane

• Few antimicrobial compounds target the cell membrane due to the similarities between bacterial and human membranes, leading to difficulties in selective toxicity
• Polymyxins:
  • Polymyxin B and E (colistin) are cyclic peptides with a hydrophobic tail and positively charged amino groups
  • Act like cationic detergents, disrupting the phospholipid structure of the cell membrane
  • Form abnormal openings in the membrane, causing leakage
  • Active against gram-negative bacteria, specifically targeting negatively charged lipopolysaccharide molecules found in their outer membranes
  • Relatively neurotoxic and nephrotoxic, so used only as a last resort
  • Typically used for infections caused by multi-drug resistant Pseudomonas aeruginosa or carbapenemase-producing Enterobacteriaceae
  • Not absorbed orally, used for infantile diarrhea (colistin) and topically for eye infections, otitis externa

Antibacterial Drugs that Inhibit Protein Synthesis

• Target various sites on both the 30S and 50S ribosomal subunits, with the overall effect of blocking protein synthesis

Antibacterial Drugs that Inhibit DNA or RNA

• Quinolones:

  • Synthetic broad-spectrum antibiotics with a core of two fused six-member rings (quinolone ring)
  • Fluoroquinolones, with fluorine substitutions, are the primary quinolones used for bacterial infections
  • Inhibit bacterial DNA replication by inhibiting topoisomerase II (DNA gyrase) and topoisomerase IV, which are essential for bacterial DNA replication but absent in human cells
  • Classified into generations based on antimicrobial activity:
    • First Generation: Nalidixic acid and Cinoxacin - active against gram-negative organisms (excluding Pseudomonas species), used for uncomplicated urinary tract infections
    • Second Generation: Norfloxacin, lomefloxacin, Enofloxacin, ofloxacin, ciprofloxacin - expanded activity against Pseudomonas species and some gram-positive bacteria, used for complicated UTI, pyelonephritis, sexually transmitted diseases, prostatitis, skin and soft tissue infections
    • Third Generation: Levofloxacin, Sparfloxacin - further expanded gram-positive coverage, including penicillin-sensitive and -resistant S. pneumoniae, used for acute exacerbation of chronic bronchitis (AECB) and community-acquired pneumonia (CAP)
    • Fourth Generation: Moxifloxacin - broadest spectrum, including anaerobic coverage, used for abdominal infections, nosocomial pneumonia, pelvic infections

• Rifampicin and Rifabutin:

  • Bactericidal antibiotics from the rifamycin group
  • Inhibit RNA synthesis by inhibiting bacterial RNA polymerase, preventing mRNA production without affecting human RNA polymerase
  • Rifampicin is used primarily for tuberculosis treatment in combination with other drugs and for prophylaxis in close contacts of meningitis patients
  • Given in combination due to the rapid emergence of resistant mutants
  • Excreted in high concentrations in saliva, making it effective for bacterial meningitis prophylaxis due to the carriage of organisms in the throat

Antibacterial Drugs that Affect Metabolic Pathways

• Sulfonamides and Trimethoprim:
  • Synthetic drugs that interfere with folate metabolism by blocking enzymes needed for tetrahydrofolate synthesis
  • Tetrahydrofolate is essential for the synthesis of folic acid, DNA, RNA, and amino acids
  • Often given together to achieve a bactericidal synergistic effect
  • Orally active and interfere with dihydrofolate reductase, an enzyme crucial for tetrahydrofolate formation

Bacterial Cell Wall

• Most bacteria contain a rigid peptidoglycan layer in their cell wall, which protects the cell from rupture in hypotonic environments.
• Peptidoglycan biosynthesis occurs in three stages:
  • Stage 1: Cell wall precursors are synthesized in the cytoplasm.
  • Stage 2: Precursors are inserted into the cell wall by a transglycosylase.
  • Stage 3: Precursors are fused by a transpeptidase.
• Mammalian cells lack cell walls, making antibiotics targeting peptidoglycan synthesis highly selectively toxic. They only target bacterial cells.
• Antibiotics targeting cell wall synthesis are most effective against actively growing microorganisms.
• Antibiotics targeting cell wall synthesis cause the cell to develop weak points and become osmotically fragile.
• These antibiotics are considered bactericidal because the weakened cell is susceptible to lysis.

β-Lactam Antibacterials

• β-Lactam antibiotics are characterized by the presence of a β-lactam ring in their structure, essential for antibacterial activity.
• This group includes penicillins, cephalosporins, carbapenems, and monobactams.
• They interfere with the transpeptidation reactions that seal the peptide crosslinks between glycan chains.
• β-Lactam antibiotics inhibit penicillin-binding proteins (PBPs), which are enzymes responsible for cross-linking in bacterial cell walls.

Penicillins

• Penicillin antibiotics are a large group of compounds ending in the suffix "-cillin".
• Benzyl penicillin (Penicillin G) is the parent compound, and its action is restricted to gram-positive bacteria.
• Natural penicillins (Penicillin G and Penicillin V) are produced by fermentation of the fungus Penicillium rubens.
• Semisynthetic penicillins, like amoxicillin and ampicillin, are created by chemically modifying the main nucleus.

Penicillin Properties

• Penicillin G is the best choice for sensitive bacteria due to its low toxicity and low cost. However, it can be hydrolyzed by β-lactamases and acids, is rapidly excreted in urine, and can trigger allergies.
• Amoxicillin is a broader-spectrum penicillin that has a good oral bioavailability and is well-tolerated. It exhibits excellent activity against a wide range of gram-positive and gram-negative bacteria.
• Ampicillin has a longer half-life than amoxicillin and is considered to be more effective against a broader range of bacteria. It is often used for meningitis and other serious infections.

This quiz explores the properties and mechanisms of glycopeptides, including vancomycin and teicoplanin. It discusses their action on cell wall synthesis, effectiveness against gram-positive bacteria, and their use in treating infections. Additionally, it covers lipoglycopeptides and their clinical relevance.