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Antimicrobial agents
Chapter 33
Term | Definition |
---|---|
Selective toxicity | The antimicrobial agents should act at a target site present in the infecting organism, but absent from host cells |
Antibiotic | Natural metabolic products of fungi, actinomycetes and bacteria that kill or inhibit the growth of micro-organisms |
Antibacterial agents classification (3) | 1. according to whether they are bactericidal or bacteriostatic 2. by their target site 3. by their chemical structure |
Difference between bactericidal and bacteriostatic | Bactericial agents kill the bacteria and is irreversible, while bacteriostatic agents inhibit bacteria growth and is a reversible process |
5 main target sites for antibacterial action | 1. cell wall synthesis 2. protein synthesis 3. nucleic acid synthesis 4. metabolic pathway 5. cell membrane function |
Resistant organism | An organism that will not be inhibited or killed by an antibacterial agent at concentrations of the drug achievable in the body after normal dosage |
Inhibitors of cell wall syntesis antibacterial classes (2) | Beta-lactams and Glycopeptides |
Anti-bacterial mechanism of beta-lactams | Inhibits cell wall synthesis by binding to PBPs and inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls |
Penicillin-binding proteins (PBPs) | Membrane proteins capable of binding to penicillin and are responsible for the final stage of crosslinking of the bacterial cell wall structure |
Result of inhibition of peptidoglycan layer syntheisis(3) | Accumulation of precursor cell wall units, leading to activation of the cell's autolytic system and cell lysis |
Bacterial species not susceptible to beta lactams + example(3) | Species that lack a cell wall (mycoplasma), species with very impermeable cell wall (mycobacteria) or intracellular pathogens (chlamydia) |
Five members of beta lactam family | Penicillins (G+), cephalosporins (G+), Cephamycins (G+), Carbapenems (G-/+) and Monobactams (G-) |
Mechanisms to become beta-lactam resistant (3) | Alteration of PBP target site, altering the access to the PBP target site and production of beta-lactamases |
Mechanism to alter PBP target site + bacterial species | Staphyloccus Aureus has a mecA gene in his chromosome which encodes for PBP2a with lower affinity for beta-lactams |
Mechanism to inhibit access to PBP target site + bacteria class | Mutation in porin genes result in decrease in permeability of the outermembrane of gram-negative cells. No more diffusion of beta lactams through porins in outer membrane |
Beta-lactamases + location | Enzymes that catalyze the hydrolysis of the beta-lactam ring to generate inactive products. Found on chromosomes and on plasmids |
Difference between beta lactamase in Gram + and - bacteria | Beta lactamases of Gram + are released into the extracellular environment and beta lactamases of Gram - bacteria remain whithin the periplasm |
Beta-lactamase inhibitors | Molecules that contain a beta-lactam ring, and binds to beta-lactamases hereby preventing them from destroying beta-lactams |
Glycopeptides | Bactericidal compounds that interfere with cell wall synthesis by binding to terminal D-alanine-D-alanine at the end of pentapeptide chains which are part of the growing bacterial cell wall structure |
Glycopeptide antibiotics + usage | Vancomycin and Teicoplanin are active only against Gram + bacteria and are used to treat beta lactam resistant Gram + rods and coccus and patients allergic to beta lactam |
Glycopeptide resistance genes + mechanisms | vanA, vanB and vanD encode for a ligase that produces a pentapeptides that terminate in D-alanine-D-lactate |
vanA characteristics and location | VanA causes high inducible resistance to vancomycin and teicoplanin adn can be found on chromosomes and plasmids |
vanB characteristics and location | VanB causes high inducible resistance to vancomycin but NOT teicoplanin and is chromocal and plasmid linked |
vanD characteristics and location | vanD is chromocomal and non-transferable resulting in constitutice resitance to high levels of vancomycin but low levels of teicoplanin |
Inhibitors of protein synthesis antibacterial classes (6) | 1. Aminoglycosides 2. Tetracyclines 3. Chloramphenicol 4. Macrolides, lincosamides and Streptogramins 5. Oxazolidones 6. Fusidic acid |
Aminoglycosides antibiotics (2) + treatment | Gentamycin is important for the treatment of serious Gram - infection. Streptomycin is important for the treatment of mycobacterial infections |
Aminoglycosides mechanism one | Binds to specific proteins in the 30S ribosomal subunit, and interferes with the binding of fmet-tRNA to the ribosome, thereby preventing the formation of initiation complexes from which protein synthesis proceeds |
Aminoglycosides mechanism two | They cause misreading of mRNA codons and tend to break apart functional polysomes into non-functional monosomes |
Aminoglycosides resistance mechanisms (4) | 1. alteration of the 30S ribosomal target protein 2. alteration in cell wall permeability 3. alteration in the energy-dependent transport accross the cytoplasmic membrane 4. production of resistant enzymes |
Aminoglycoside resistant enzymes (3) + mechanism and location | Acetylase, adenylylase and phosphorylase alter the structure of the aminoglycoside molecule and inactivates the drug. They are often plasmid-mediated |
Tetracycline + mechanism | Bacteriostatic compound that inhibit protein synthesis by binding to the small ribosomal subunit in a manner that prevents aminoacyl tranfer RNA from entering the acceptor sites on the ribosome |
Tetracyclines treatment | Tetracyclines are used in the treatment of infections caused by mycoplasmas, chlamydiae and rickettsiae |
Tetracycline resistant genes + mechanisms and location | Resistance genes are carried on a transposon and cause the synthesization of new cytoplasmic proteins in the presence of tetracycline. The tetracyclin is then positively pumped out of resistant cells (efflux mechanism) |
Chloramphenicol + mechanisms | This compound binds to the 50S ribosomal subunit and blocks the action of peptidyl transferase and hereby prevents peptide bond synthesis |
Chloramphenicol treatment | It is used in the treatment of bacterial meningitis, aerobes and anaerobes, including intracellular organisms |
Chloramphenical resistance genes | Chloramphenicol acetyl transferases are intracellular, but are capable of inactivating all chloramphenicol in the immediate environment of the cell. Acetylated chloramphenicol fails to bind to the ribosomal target. |
Macrolides, lincosamides and streptogramins form a group | They share overlapping binding sites on ribosomes, and resistance to macrolides confers resistance to the other two classes |
Macrolides, lincosamides and streptogramins mechanism | They bind to the 50S ribosomal subunit (23S rRNA) and block the translocation step in protein synthesis, thereby preventing the releasing of tRNA after peptide bond formation |
Oxazolidinones + mechanisms | Oxazolidinones are active against Gram + bacteria and inhibit the initiation of protein synthesis by targeting 23S rRNA in the 50S subunit in a manner which prevents formation of a functional 70S complex |
Fusidic acid + mechanisms | Bacteriostatic agent that inhbits the protein synthesis by forming a stable complex with elongation factor G (EF-G), guanosine diphosphate and the ribosome |
Inhibitors of nucleic acid antibacterial classes (4) | 1. Quinolones 2. Rifamycins 3. Sulphonamides 4. Trimethoprim |
Quinolones + mechanisms | Bactericidal synthetic agents that inhibit the activity of bacterial DNA gyrase and topoisomerase |
DNA gyrase | DNA gyrase produces and removes supercoils in DNA ahead of the replication fork to maintain the proper tension required for efficient DNA duplication |
Topoisomerase | Topoisomerase acts to remove supercoils and to seperate newly formed DNA daugther strands after replication |
Quinolones chromosomal mediated resistance (3) | 1. mutations that alter the target enzyemes 2. alteration in cell wall permeability 3. efflux |
Quinolones plasmid-mediated resistance (1) | Production of a protein that protects the target DNA from quinolone binding |
Rifamycins + mechanisms | Bactericidal molecules that binds to the DNA-dependent RNA polymerase and blocks the synthesis of mRNA |
Rifamycins resistance | Chromosomal mutation that alter the RNA polymerase target, which then has lower affinity for the Rifamycin and escapes inhibition |
Sulphonamides + mechanisms | Bacteriostatic compounds that act in competition with PABA, for the active site of dihydropteroate synthetase, an enzyme that catalyses an essential reaction in the synthetic pathway of THFA |
THFA | THFA is required for the synthesis of purines and pyrimidines |
Sulphonamide resistance | Plasmid-mediated genes encode for an altered dihydropteroate synthetase. This is essentially unchanged in its affinity for PABA, but has a greatly decreased affinity for the sulphonamide |
Trimethoprim + mechanism | Trimethoprim prevents THFA synthesis by inhibiting dihydrofolate reductase |
Trimethoprim resistance | Plasmid-encoded dihydrofolate reductases with altered affinity for trimethoprim |
Inhibitors of cytoplasmic mebrane functions antibacterial classes (2) | Lipopeptides and Polymexins |
Lipopeptides | Lipopeptides acts in a calcium-dependent matter to insert and depolarize the bacterial cytoplasmic membrane. This then causes inability to synthesize ATP and interference in the uptake of nutrients |
Polymexins | Polymexins are bactericidal cyclic polypeptides. The free amino groups act as cationic detergents, disruption the phospholipid structure of the cell membrane. |
Polymexins resistance | Chromosomally-mediated alterations in membrane structure or antibiotic uptake |