BACTE: ACTIONS OF ANTIMICROBIAL

• Antibiotics - are hemical substances that are produced by microorganisms that have the capacity to inhibit or kill other microorganisms.
• Antibiotics: may be classified as broad spectrum or narrow spectrum
• Antibiotics: May be classified as either natural, semi-synthetic, or synthetic drugs
• Antibiotics: May be either bacteriostatic or bactericidal
• Minimum-inhibitory concentration (MIC) – the lowest concentration of a drug that can inhibit bacterial growth
• Minimum-bactericidal concentration (MBC) – the lowest concentration of a drug that can still kill bacteria
• Therapeutic index – the ratio of toxic dose to the therapeutic dose; the higher the index, the more effective the chemotherapeutic agent
• Characteristics of Antimicrobial Agents: must be in active form
• Characteristics of Antimicrobial Agents: must be able to achieve concentration at the site of infection that is higher than the pathogen’s MIC to be effective
• Characteristics of Antimicrobial Agents: selective toxicity
• Types of Antimicrobial Agents: Cell wall inhibitors - selective antibiotics with a high therapeutic index
• Types of Antimicrobial Agents: Cell wall inhibitors - interferes with the biosynthesis of peptidoglycan
• Types of Antimicrobial Agents: Cell wall inhibitors - beta-lactam antibiotics form covalent complexes with enzymes that generate mature peptidoglycan molecules (transpeptidase enzymes that mediate peptidoglycan cross-linking) - active component of the beta-lactam family of drugs is the beta-lactam structure
• Types of Antimicrobial Agents: Cell wall inhibitors - Glycopeptides inhibit cell wall synthesis by binding to the end of the peptidoglycan, preventing transpeptidation
• Peptidoglycan is a structure composed of an alternating disaccharides N-acetyl-glucosamine and N-acetyl-muramic acid.
• The cross linking provides strength to the mature cell wall and this is catalyzed by transpeptidase enzymes (also called Penicillin-binding proteins or PBP).
• Glycopeptides is a group of antibiotics that also prevent cell wall synthesis by binding to the components of the peptidoglycan, preventing cell wall synthesis.
• Types of Antimicrobial Agents: Inhibitors of Folate Synthesis - folic acid pathway provides essential precursor molecules needed for DNA biosynthesis
• Types of Antimicrobial Agents: Inhibitors of Folate Synthesis - Sulfamethoxazole/SMZ (a sulfonamide) prevents the formation of dihydropteroate through competitive inhibition of para-aminobenzoic acid with the enzyme dihydropteroate synthase
• Types of Antimicrobial Agents: Inhibitors of Folate Synthesis - Trimethoprim blocks the formation of the tetrahydrofolate by inhibiting dihydrofolate reductase
• The synthesis of folate is necessary for the production of purines, a component of the DNA.
• Sulfamethoxazole, a sulfonamide, competes with the substrate p-amino benzoic acid in binding with the enzyme dihydropteroate synthase.
• Trimethoprim, on the other hand, competes with the enzyme dihydrofolate reductase.
• Types of Antimicrobial Agents: Agents that interfere with DNA replication - Topoisomerases I, II, III, and IV are necessary for DNA replication
• Types of Antimicrobial Agents: Agents that interfere with DNA replication - Quinolones affect DNA replication by targeting topoisomerases II (DNA gyrase) in gram negative bacteria and Topoisomerase IV in gram-positive bacteria
• Types of Antimicrobial Agents: Agents that interfere with DNA transcription - Transcription of DNA into RNA is mediated by RNA polymerase
• Types of Antimicrobial Agents: Agents that interfere with DNA transcription - Rifampin targets the RNA polymerase subunit, blocking RNA chain elongation
• DNA replication is a process in which the DNA is duplicated in preparation for cell division. The enzymes topoisomerases I, II, III, and IV necessary for DNA replication.
• Quinolones are antibiotics know to target these enzymes and prevent the process. In gram positive bacteria, quinolones target the topoisomerase IV enzyme, while in gram negative bacteria, topoisomerase II (aka as DNA gyrase) is inhibited.
• DNA transcription, or the synthesis of RNA using a strand of DNA as a template, is mediated by RNA polymerase. This enzyme is inhibited by the antibiotic rifampin, disabling the elongation of the RNA chain
• Types of Antimicrobial Agents: Agents that inhibit protein synthesis - Some antibiotics target the 30S ribosomal subunit (aminoglycosides, spectinomycin, tetracyclines, glycylcyclines)
• Types of Antimicrobial Agents: Agents that inhibit protein synthesis - Others target the 50S ribosomal subunit (macrolides, lincosamides, chloramphenicol, oxazolidinones, streptogramins)
• Types of Antimicrobial Agents: Agents that inhibit protein synthesis - Only aminoglycosides are bactericidal; the rest are bacteriostatic
• Types of Antimicrobial Agents: Agents that inhibit protein synthesis - Aminoglycosides, chloramphenicol, and tetracycline have side effects
• Antibiotics are also know to inhibit protein synthesis by binding to the subunits of the ribosomes.
• Some antibiotics such as aminoglycosides and tetracyclines, attack the 30S ribosomal subunit resulting in the misreading of the mRNA.
• Others such as macrolides and chloramphenicol have affinity against the 50S subunit, resulting in the inhibition of peptide chain elongation.
• Aminoglycosides may cause deafness and loss of balance.
• Chloramphenicol may cause temporary or permanent depression of the bone marrow that leads to aplastic anemia and leukopenia.
• Impermeability - Antibiotics must be able to penetrate the cell wall to reach their targets.