Robert A. Nichols, Ph.D. INTRODUCTION TO ANTIBACTERIAL ...

INTRODUCTION TO ANTIBACTERIAL AGENTSRobert A. Nichols, Ph.D.Reading: Rang & Dale’s Pharmacology, 6 th Edition, 2007, Chapter 45Objectives:1. To understand the basic mechanisms of action of the major antibacterial agents:cell wall inhibitors, protein synthesis inhibitors, biosynthetic pathways inhibitors2. To understand the mechanisms underlying resistance to antibacterials:change in permeability, efflux, metabolism, mutation, overexpression3. To know the major adverse effects of different classes of antibacterials:toxicity, hypersensitivitySelective ToxicityAntibacterials, or more commonly “antibiotics” are among the least directly toxic agentsin use as drugs for treatment of bacterial infections in vertebrates. Hence, these drugs exerthighly ‘selective’ toxicity. Typically, they act either as:bacteriostatic agents = suppress the growth of a given pathogenic organism, orbacteriocidal agents = directly kill a given organismClasses of antibacterials based on selectivity(know the distinctions without worrying which are Class I, II or III)1. Selectivity based on accumulation6 drug may act on both mammalian and bacterial systems, but is only takenup by bacteria to any significant extent.Example: tetracycline (actively taken up by bacteria; poorly permeatesmammalian plasma membranes)2. Selectivity based on distinct biochemical pathways6 drug may act on step in synthetic pathway unique to certain bacteria.Example: sulfonamides (block folate biosynthesis)6 drug may block bacterial protein synthesis.Example: chloramphenicol (blocks peptidyl transferase by binding to 50Sbacterial ribosome)6 drug may exploit lack of metabolic pathways handling toxic compounds.Example: metronidazole (precursor to toxic oxidant, inactivated in mammals by residentantioxidants)

3. Selectivity based on cytology6 drug may act selectively on bacterial cell wall.Example: penicillin (blocks peptidoglycan crosslinking step in cell wallsynthesis)Classes of antibacterials based on mechanism of action1. Inhibitors of bacterial cell wall synthesis:6 different groups of antibiotics in this class act at different steps in the biosynthesisof the bacterial cell wall peptidoglycan layer• Peptidoglycan layer synthesized from polymers of alternating sugars, one of which- N-acetylmuramic acid (M) - has pentapeptide side chains that link the polymersvia pentaglycine bridges added by a transpeptidation reaction:

• Various cell wall synthesis inhibitors act at: initial pentapeptide side chainformation; transfer of peptidoglycan subunits to growing layer; transglycosylation;transpeptidation6 Example: pencillins are structural analogs of D-Ala-D-Ala and inhibittranspeptidation; vancomycin binds to the terminal D-Ala-D-Ala, preventing furtherpeptidyl crosslinking2. Inhibitors of bacterial protein synthesis:6 these antibiotics act at different sites in the ribosomal protein synthesis complex• Aminoglycosides appear to act at several sites: block initiation complex; causemisreading of mRNA resulting in wrong amino acid being incorporated; blocktranslocation[for simplicity, only 2 t-RNA interaction sites are shown on the ribosome: donor andacceptor, fitting with more traditional, basic representations]3. Inhibitors of bacterial biosynthetic pathways6 one group blocks folate biosynthesisp-Aminobenzoic acid (PABA) 6 Dihydrofolate 6 Tetrahydrofolate 6 Purines 6 DNA8 8Sulfonamides Trimethoprim

Adverse Effects1. Direct toxic effectsA. Kidney:6 Aminoglycosides are nephrotoxic. As the kidney is the major route forclearance of aminoglycosides, impaired renal function with continued use willlead to increased plasma levels.6 Sulfonamides may form crystals in urinary tract, due to their poor solubilityB. Nervous system:6 Penicillin G may cause generalized motor seizures if plasma levels areunusually high (eg. under conditions of impaired renal function).6 Cephalosporins with MTT-substituent can cause a ‘disulfiram reaction’ inindividuals who ingest alcohol (violent vomiting)6 Aminoglycosides can cause neuromuscular blockade via an action on themotor nerve endings. [Issue postoperatively]C. Auditory system:6 Aminoglycosides at high levels are ototoxicD. Bone marrow:6 Chloramphenicol is toxic to human bone marrow cells (can lead to aplasticanemia)E. Teeth:6 Tetracycline can permanently stain teeth (brown) when given to children.2. HypersensitivityA. Rashes to anaphylactic shock:6 Penicillins and CephalosporinsB. Vasculitis:6 Sulfonamides (not common; primarily in elderly)