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Microbiology Babylon university 2nd stage pharmacy collage Inhibition of Cell Wall Synthesis Bacteria have a rigid outer layer, the cell wall. The cell wall maintains the shape and size of the microorganism, which has a high internal osmotic pressure. Injury to the cell wall (eg, by lysozyme) or inhibition of its formation may lead to lysis of the cell. In a hypertonic environment (eg, 20% sucrose), damaged cell wall formation leads to formation of spherical bacterial "protoplasts" from gram-positive organisms or "spheroplasts" from gramnegative organisms; these forms are limited by the fragile cytoplasmic membrane. If such protoplasts or spheroplasts are placed in an environment of ordinary tonicity, they take up fluid rapidly, swell, and may explode. Specimens from patients being treated with cell wall-active antibiotics often show swollen or misshapen bacteria. The cell wall contains a chemically distinct complex polymer "mucopeptide" ("peptidoglycan") consisting of polysaccharides and a highly cross-linked polypeptide. The polysaccharides regularly contain the amino sugars Nacetylglucosamine and acetylmuramic acid. The latter is found only in bacteria. To the amino sugars are attached short peptide chains. The final rigidity of the cell wall is imparted by cross-linking of the peptide chains (eg, through pentaglycine bonds) as a result of transpeptidation reactions carried out by several enzymes. The peptidoglycan layer is much thicker in the cell wall of gram-positive than of gram-negative bacteria. All β-lactam drugs are selective inhibitors of bacterial cell wall synthesis and therefore active against growing bacteria. This inhibition is only one of several different activities of these drugs, but it is the best understood. The initial step in drug action consists of binding of the drug to cell receptors (penicillinbinding proteins; PBPs). There are three to six PBPs (MW 4–12 x 105), some of which are transpeptidation enzymes. Different receptors have different affinities for a drug, and each may mediate a different effect. For example, attachment of penicillin to one PBP may result chiefly in abnormal elongation of the cell, whereas attachment to another PBP may lead to a defect in the periphery of the cell wall, with resulting cell lysis. PBPs are under chromosomal control, and mutations may alter their number or their affinity for β -lactam drugs. After a β -lactam drug has attached to one or more receptors, the transpeptidation reaction is inhibited and peptidoglycan synthesis is blocked. The next step probably involves removal or inactivation of an inhibitor of autolytic enzymes in the cell wall. This activates the lytic enzyme and results in lysis if the environment is isotonic. In a markedly hypertonic environment, the microbes change to protoplasts or spheroplasts, covered only by the fragile cell membrane. In such cells, synthesis of proteins and nucleic acids may continue for some time. The inhibition of the transpeptidation enzymes by penicillins and cephalosporins may be due to a structural similarity of these drugs to acyl-D1 Microbiology Babylon university 2nd stage pharmacy collage alanyl-D-alanine. The transpeptidation reaction involves loss of a D-alanine from the pentapeptide. The remarkable lack of toxicity of β -lactam drugs to mammalian cells must be attributed to the absence, in animal cells, of a bacterial type cell wall, with its peptidoglycan. The difference in susceptibility of gram-positive and gramnegative bacteria to various penicillins or cephalosporins probably depends on structural differences in their cell walls (eg, amount of peptidoglycan, presence of receptors and lipids, nature of cross-linking, activity of autolytic enzymes) that determine penetration, binding, and activity of the drugs. Resistance to penicillins may be determined by the organism's production of penicillin-destroying enzymes (β -lactamases). Beta-lactamases open the β lactam ring of penicillins and cephalosporins and abolish their antimicrobial activity. Beta-lactamases have been described for many species of grampositive and gram-negative bacteria. Some β -lactamases are plasmidmediated (eg, penicillinase of Staphylococcus aureus), while others are chromosomally mediated (eg, many species of gram-negative bacteria). All of the more than 30 plasmid-mediated β -lactamases are produced constitutively and have a high propensity to move from one species of bacteria to another (eg, β -lactamase-producing Neisseria gonorrhoeae, Haemophilus influenzae, and enterococci). Chromosomally mediated β -lactamases may be constitutively produced (eg, bacteroides, acinetobacter), or they may be inducible (eg, enterobacter, citrobacter, pseudomonas). There is one group of β -lactamases that is occasionally found in certain species of gram-negative bacilli, usually Klebsiella pneumoniae and Escherichia coli. These enzymes are termed extended-spectrum β lactamases (ESBLs) because they confer upon the bacteria the additional ability to hydrolyze the β -lactam rings of cefotaxime, ceftazidime, or aztreonam. The classification of β -lactamases is complex, based upon the genetics, biochemical properties, and substrate affinity for a β -lactamase inhibitor (clavulanic acid). Clavulanic acid, sulbactam, and tazobactam are β lactamase inhibitors that have a high affinity for and irreversibly bind some β lactamases (eg, penicillinase of Staphylococcus aureus) but are not hydrolyzed by the β -lactamase. These inhibitors protect simultaneously present hydrolyzable penicillins (eg, ampicillin, amoxicillin, and ticarcillin) from destruction. Certain penicillins (eg, cloxacillin) also have a high affinity for β lactamases. There are two other types of resistance mechanisms. One is due to the absence of some penicillin receptors (penicillin-binding proteins; PBPs) and occurs as a result of chromosomal mutation; the other results from failure of the β -lactam drug to activate the autolytic enzymes in the cell wall. As a result, the organism is inhibited but not killed. Such tolerance has been observed especially with staphylococci and certain streptococci. 2 Microbiology Babylon university 2nd stage pharmacy collage Examples of agents acting by inhibition of cell wall synthesis are penicillins, the cephalosporins, vancomycin, and cycloserine. Several other drugs, including bacitracin, teicoplanin, vancomycin, ristocetin, and novobiocin, inhibit early steps in the biosynthesis of the peptidoglycan. Since the early stages of synthesis take place inside the cytoplasmic membrane, these drugs must penetrate the membrane to be Inhibition of Cell Membrane Function The cytoplasm of all living cells is bounded by the cytoplasmic membrane, which serves as a selective permeability barrier, carries out active transport functions, and thus controls the internal composition of the cell. If the functional integrity of the cytoplasmic membrane is disrupted, macromolecules and ions escape from the cell, and cell damage or death ensues. The cytoplasmic membrane of bacteria and fungi has a structure different from that of animal cells and can be more readily disrupted by certain agents. Consequently, selective chemotherapy is possible. Detergents, which contain lipophilic and hydrophilic groups, disrupt cytoplasmic membranes and kill the cell. One class of antibiotics, the polymyxins, consists of detergent-like cyclic peptides that selectively damage membranes containing phosphatidylethanolamine, a major component of bacterial membranes. A number of antibiotics specifically interfere with biosynthetic functions of the cytoplasmic membranes—for example, nalidixic acid and novobiocin inhibit DNA synthesis, and novobiocin also inhibits teichoic acid synthesis. A third class of membrane-active agents is the ionophores, compounds that permit rapid diffusion of specific cations through the membrane. Valinomycin, for example, specifically mediates the passage of potassium ions. Some ionophores act by forming hydrophilic pores in the membrane; others act as lipid-soluble ion carriers that behave as though they shuttle back and forth within the membrane. Ionophores can kill cells by discharging the membrane potential, which is essential for oxidative phosphorylation, as well as for other membrane-mediated processes; they are not selective for bacteria but act on the membranes of all cells. Daptomycin is a new lipopeptide antibiotic that is rapidly bactericidal by binding to the cell membrane in a calcium-dependent manner causing depolarization of bacterial membrane potential. This leads to intracellular potassium release. Currently this agent is approved for use in the treatment of skin and soft tissue infections caused by gram-positive bacteria, particularly those organisms that are highly resistant to β -lactam agents and vancomycin. Other examples of agents acting by inhibition of cell membrane function are amphotericin B, colistin, and the imidazoles and triazoles 3