Cell Wall Synthesis Inhibitors

Cell Wall Synthesis Inhibitors

• Bacteria like Staphylococcus aureus and Enterococcus have developed resistance to antibiotics by replacing the terminal D-alanine residue with D-lactate or D-serine, altering the drug target.
• Bacitracin is a group of structurally similar peptide antibiotics that block the dephosphorylation of C55-isoprenyl pyrophosphate and bactoprenol pyrophosphate, which are membrane carrier molecules that transport peptidoglycan precursors from the cytoplasm to the cell exterior.
• Bacitracin prevents the incorporation of peptidoglycan precursors into the cell wall, has a broad spectrum, and is effective against gram-positive organisms on the skin, including Staphylococcus and Streptococcus.
• However, Bacitracin has been shown to be nephrotoxic (damaging to the kidneys) and is commonly found in combination with neomycin and polymyxin in topical ointments.

Polymyxin

• Polymyxin is a cyclic polypeptide that inserts into the cell membrane, increasing its permeability and leading to cell death.
• It is most active against gram-negative rods, and is particularly valuable against Pseudomonas aeruginosa and other gram-negative bacilli.
• Polymyxin may be combined with gramicidin, which also increases cell membrane permeability.

Fundamentals

Drug Interactions

• Sometimes, two drugs administered together may provide a synergistic interaction that is better than the efficacy of either drug alone.
• An example of this is trimethoprim and sulfamethoxazole, which are individually bacteriostatic but are bactericidal when combined.
• Antagonistic interactions, on the other hand, can produce harmful effects, such as loss of drug activity, and can occur between two antimicrobials or between antimicrobials and non-antimicrobials being used to treat other conditions.
• The effects of antagonistic interactions can vary depending on the drugs involved, and can cause a range of problems, including decreased absorption of antimicrobials.

Antibiotics

Protein Synthesis Inhibitors

• 80S cytoplasmic ribosomes in animal cells are structurally distinct from those found in bacterial cells (70S), making protein synthesis a good selective target for antibacterial drugs.
• Protein synthesis inhibitors can affect different steps in protein synthesis, including aminoacyl-tRNA binding, peptide bond formation, mRNA reading, and translocation.
• The therapeutic index of protein synthesis inhibitors is fairly high, but not as high as that of cell wall inhibitors.

Ribosome Structure

• Bacterial ribosomes have a 70S structure, consisting of a 50S subunit and a 30S subunit.
• Animal ribosomes have a 80S structure, consisting of a 60S subunit and a 40S subunit.

Aminoglycosides

• Aminoglycosides contain a cyclohexane ring and amino sugars, and are effective against gram-negative bacteria and Mycobacterium.
• Examples of aminoglycosides include streptomycin, gentamycin, kanamycin, neomycin, and tobramycin.
• Aminoglycosides attach irreversibly to the 30S subunit of bacterial ribosomes, blocking the reading of the genetic code on mRNA and inhibiting peptide elongation.
• They are toxic and can cause deafness, renal damage, loss of balance, nausea, and allergic reactions.
• Aminoglycosides impair the proofreading ability of the ribosomal complex, causing mismatches between codons and anticodons, and resulting in the production of proteins with incorrect amino acids.
• These faulty proteins are inserted into the cell membrane, disrupting it and ultimately leading to cell death.

Historical Perspectives

• Antimicrobials have been used for millennia for the treatment of various infections, with examples including ancient Egyptian use of mouldy bread to treat infected wounds, and Central Asian use of mouldy chewed barley and apple paste.
• Paul Ehrlich, known as the father of chemotherapy, discovered the concept of a "magic bullet" and developed Salvarsan, a synthetic chemical that was specific for disease-causing microbes.
• Ehrlich's work established the modern chemotherapeutic era, which involves systematic chemical synthesis with subsequent activity checks.