Supervisor:Dr.M.Aslanimehr Presented by :M.Marandi

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1 Journal Club & MSc Seminar anti adhesin therapy Supervisor:Dr.M.Aslanimehr Presented by :M.Marandi

2 The first stage of microbial infection colonization: the establishment of the pathogen at the appropriate portal of entry. Pathogens usually colonize host tissues that are in contact with the external environment. Adherence : is an essential step in bacterial pathogenesis or infection, required for colonizing a new host. 2

3 receptor carbohydrate or peptide residues on the eucaryotic cell surface ligand macromolecular component of the bacterial cell surface adhesin 3

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5 Mechanisms of Adherence to Cell or Tissue Surfaces The mechanisms for adherence may involve two steps: nonspecific adherence: reversible attachment of the bacterium to the eucaryotic surface (sometimes called "docking") specific adherence: reversible permanent attachment of the microorganism to the surface (sometimes called "anchoring"). 5

6 Nonspecific adherence 6

7 Specific adherence High affinity bacterial host cell interactions permanent formation many specific lock-andkey bonds between complementary molecules on each cell surface. Complementary receptor and adhesin molecules must be accessible and arranged in such a way that many bonds form over the area of contact between the two cells. Irreversible 7

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9 Lectin (LTA) Ligand (LPS) Mucous Capsule Glycocalyx Specific Adherence of Bacteria to Cell and Tissue Surfaces Fimbriae Common pili S-layer Sex pilus Type 4 pili Type 1 fimbriae 9

10 Specific Adherence of Bacteria to Cell and Tissue Surfaces Tissue tropism S. mutans S. salivarius Species specificity N. gonorrhoeae Group A streptococcal Genetic specificity within a species pigs are not susceptible to E. coli K-88 infections 10

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13 Adhesion (of the bacterium to the eucaryotic cell surface) is inhibited by: Isolated adhesin or receptor molecules Adhesin or receptor analogs Enzymes and chemicals that specifically destroy adhesins or receptors Antibodies specific to surface components 13

14 Impairing pathogen receptor biogenesis sub-inhibitory concentrations of certain antibiotics; fluoroquinolone aminoglycoside altered physicochemical properties of the bacterial surface and decreased bacterial adhesion This is thought to be caused by aberrant protein synthesis leading to the production of partially or incorrectly folded proteins and thus impaired surface display of outer membrane proteins and assembly of fimbrial adhesins. 14

15 Inhibition of host receptor biogenesis Many bacterial adhesins and toxins rely on host glycosphingolipids (GSLs) for host cell binding and membrane translocation and depletion of GSLs from the host cell membrane has been proposed as an efficient strategy to prevent or treat infections. 15

16 Inhibition of host receptor biogenesis glucosyl ceramide glycosphingolipid glycosyltransferase 16

17 Use of Receptor Analogs in Competition-Based Strategies 17

18 Use of Receptor Analogs in Competition-Based Strategies Sugar-based inhibitors and glycomimetics Peptide-based inhibitors 18

19 Sugar-based inhibitors and glycomimetics Specific bacterial host interactions are frequently mediated by carbohydrates, which are present in large numbers both on the: bacterial surface capsules lipopolysaccharides glycoproteins host surface glycoproteins glycosphingolipids 19

20 E. coli (UPEC) Tip of type 1 pili Sugar-based inhibitors and FimH,the adhesive subunit at the tip glycomimetics a bacterial lectin recognizing mannosylated uroplakins and N- linked oligosaccharides luminal surface of the bladder. 20

21 Sugar-based inhibitors and glycomimetics FimH is a key virulence factor in UTIs and is crucial for multiple stages of infection, such as colonization and invasion of bladder tissue as well as formation of intracellular bacterial communities which are responsible for disease recurrence. The interaction of FimH with host cells has thus long been a target for the development of antiadhesives. 21

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23 Sugar-based inhibitors and glycomimetics Many of the body s endogenous defense mechanisms against bacterial infection are based on sugars, which act as decoys for bacterial surface receptors. For example, mucus is secreted by the intestinal epithelium and acts as a physical barrier against colonization by enteropathogens. Mucus contains a variety of mucin glycoproteins and the glycosylation pattern of mucins mimics the pattern found in epithelial surface receptors. 23

24 Sugar-based inhibitors and glycomimetics Mucins act by binding and immobilizing bacteria, which are subsequently cleared from the gastrointestinal tract by shedding of the mucus layer. This strategy has been adapted for therapeutic use. bovine Muc1, a highly glycosylated mucin derived from cow milk, efficiently prevents bacterial infection of cultured intestinal epithelial cells. Muc1 selectively inhibits the attachment of gram-negative pathogens (E. coli and Salmonella Typhimurium) 24

25 Peptide-based inhibitors Streptococcus mutans, one of the main causative agents of dental caries, expresses a surface protein streptococcal antigen (SA) I/II that binds to salivary receptors adsorbed on the hydroxyapatite matrix of the tooth surface. SA I/II is the key attachment factor of S. mutans and monoclonal antibodies raised against SA I//II can prevent tooth colonization and caries in nonhuman primates as well as colonization of the oral cavity in humans. 25

26 Advantages of Anti-Adhesion Therapy mechanism of action does not give rise to bacterial resistance. Because anti-adhesive compounds only inhibit bacterial binding without affecting microbial viability. stability under physiological conditions. Both bacterial and host receptor molecules are evolutionary adapted to withstand the physiological conditions encountered upon extracellular exposure. anti-adhesion compounds are not bactericidal. 26

27 gel Injection spray Anti adhesin Oral Oinment 27

28 cranberry juice More recently, the active compounds for some of these foods have been isolated and demonstrated to have anti-adhesive properties in vitro, underlining their effectiveness as anti-infective compounds. against bacterial infections, in particular UTIs UPEC Helicobacter pylori Porphyromonas gingivalis Their mechanism of action seems to be binding to flagella and pili, thus inhibiting bacterial surface attachment, swarming motility and aggregation into biofilms. 28

29 Bilberry; Blueberry oral anti-adhesive effects bilberry constituents can bind competitively to the same uroepithelial cells as bacteria Inhiition ability of oral bacteria to aggregate and thus colonize. 29

30 Garlic ointment inhibits biofilm formation by bacterial pathogens from burn wounds Inhibiting the growth of different bacterial pathogens. To increase the susceptibility of P. aeruginosa to tobramycin and to phagocytosis. In the murine model of lung infection, it has been shown to significantly reduce mortality rate and promote rapid clearing of P. aeruginosa from the lung. Blocks P. aeruginosa and Acinetobacter baumannii quorum sensing systems,which have been shown to control biofilm development Oinment 30

31 Biologic Effects Of Aloe Vera Gel Moisturizing actions Wound healing effects Anti-inflammatory effects Antibacterial/antifungal/antiviral effects by eliminating the bacteria that contributed to inflamation Aloe vera in dental health practice Aloe vera as denture cleanser Gel 31

32 Thank you 32