Module 4

• Selective toxicity is the use of drugs to harm an invading organism without harming the host (treat infections)
• An antibiotic is a chemical substance that suppresses the growth of bacteria, and may eventually destroy them, and is done through either bacteriostatic or bactericidal effects.
• Bacterial cells have a rigid outer layer called the cell wall that surrounds the cytoplasmic membrane. It contains a peptidoglycan layer (complex of cross-linked polymer of polysaccharides and polypeptides) giving the cell wall its rigidity and prevents it from cell lysis.
• Gram-positive bacteria have a thick peptidoglycan layer with no outer membrane.
• Gram-negative bacteria have a thin peptidoglycan layer and no outer membrane.
• Cell wall synthesis inhibitors to proper formation of bacterial cell wall and/or membrane, influencing structural integrity. Examples are penicillins and cephalosporins.
• Protein synthesis inhibitors inhibit protein translation within bacteria. Examples are tetracylines and macrolides.
• DNA synthesis inhibitors inhibit DNA replication in bacteria, preventing bacterial growth. Examples are fluoroquinolones
• Metabolic inhibitors block the formation of key bacteria metabolic substrates needed for survival and reproduction. Examples are antifolate drugs
• Penicillin G is a natural penicillin that destroys mainly gram-positive bacteria, useful for pneumonia, middle ear infections, skin infections, meningitis, and syphilis.
• Methicillin is an antibiotic resistant to attack by penicillinase produced by bacteria (to destroy penicillin).
• Ampicillin and amoxicillin are penicillin antibiotics that are broader than penicillin G and are useful against a range of infections cause by gram-negative bacteria (urinary tract infections)
• Amoxicillin and clavulanic acid is a combination of semisynthetic penicillin plus an inhibitor of penicillinase that was introduced into therapy to combat penicillinase-producing strains of bacteria.
• Penicillin acts by mimicking D-alanyl-D-alanine, a chemical component necessary for the formation of bacterial cell walls, and results in the formation of bacteria without cell walls, known as protoplasts (fragile and can burst).
• Adverse effects to penicillin include gastrointestinal distress (nausea and diarrhea) and allergy (rash, fever, face and tongue swelling, etc.)
• Cephalosporins are cell wall synthesis inhibitors that are more resistant to penicillinase than penicillin group.
• Adverse effects of cephalosporins are similar to penicillin, and include gastrointestinal side effects and allergy (uncommon)
• Fluoroquinolones are DNA synthesis inhibitors in bacteria. An example is ciprofloxacin, and is used for oral or intravenous therapy of infections caused by a wide variety of gram-positive and gram-negative microorganisms.
• Tetracyclins is a type of protein synthesis inhibitor are a type of protein synthesis inhibitor that work by binding to the 30s subunit of the ribosome complex and prevent the addition of amino acids to the protein chain, inhibiting protein synthesis.
• Adverse effects of tetracyclins include gastrointestinal effects, and discolouration of the teeth and diminished bone growth.
• Tetracyclines have a strong affinity for calcium and are used very cautiously during pregnancy or in children under 12. They can deteriorate into toxic degradation products if stored for too long. Therefore they should be discarded after long periods of time
• Macrolides are types of protein synthesis inhibitors used when someone is allergic to penicillin, effective in treating gram-positive bacteria.
• Erythromycin is a type of macrolide that is effective in treating gram-negative bacteria.
• Macrolides bind to the 50s ribosomal subunit of tRNA and block peptide bond formation.
• Adverse effects of macrolides include nausea, vomiting and diarrhea.
• Antifolates are a type of metabolic inhibitor that inhibit folate metabolism in bacteria. Tetrahydrofolic acid, a folate, is essential for bacterial to synthesize DNA and protein.
• Sulfonamides are an antifolate that inhibit an upstream step of of tetrahydrofolic acid synthesis, by inhibiting PABA, and are selectively toxic to bacteria.
• Trimethoprim are antifolates that inhibits dihydrofolic acid reductase, inhibiting the formation of tetrahydrofolic acid, and is selectively toxic to bacteria.
• Co-trimoxazole is a combination of antifolates that is useful in the treatment of urinary tract infections, respiratory tract infections, and gastrointestinal tract infections.
• Antibiotic combinations are used when the bacterial threat is not known, when the bacteria cannot be treated by one type of antibacterial, and infections that are treated by two antibacterials synergistically.
• Disadvantages of antibacterial combinations include development of antibacterial resistance, unnecessary additional costs if it can be treated by one, and increased chance of encountering toxicity.
• Development of antibiotic resistance is caused by two factors: evolution of bacteria, and clinical and environmental factors.
• Causes of antibacterial resistance include over-prescription, inappropriate use, and use in agriculture.
• Organisms can become resistant through uptake (molecules move through small pores inside the microorganism), target (reduce binding of the drug to its target), inactivation (enzyme developed to inactivate the antibiotic), and efflux pumps (overexpression of transporters that pump the drug out of the microorganism)
• Echincandins are antifungals that inhibit the synthesis of the cell wall, resulting in fungal death. Only available via intravenous administration and include micafungin and caspofungin
• Imidazoles (azoles) are antifungals useful for systemic fungal infections. They inhibit fungal cytochrome P450, inhibiting ergosterol synthesis (critical for fungal cell wall function and survival)
• A virus is a small infectious agent only capable of multiplying within the living cells of other organisms.
• Oseltamivir (Tamiflu) is an antiviral for influenza that inhibits neuraminidase which is an enzyme that allowd for the spread of the virus from cell to cell
• Acyclovir is an antiviral drug that inhibits viral DNA replication by activating acyclovir to the active form, selective to cells infected with the virus. It is the drug of choice for HSV and VZV (chickenpox and shingles)
• Hormonal contraception includes oral contraceptives, injectable contraceptives, intrauterine devices (IUD), and the transdermal patch