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M-4 Advanced Therapeutics Course

M-4 Advanced Therapeutics Course. Mechanisms of antimicrobial action directed against the bacterial cell wall and corresponding resistance mechanisms. Altered drug targets (e.g., PBPs ribosomes, DNA gyrase). Altered uptake or accumulation of

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M-4 Advanced Therapeutics Course

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  1. M-4 Advanced Therapeutics Course Mechanisms of antimicrobial action directed against the bacterial cell wall and corresponding resistance mechanisms

  2. Altered drug targets (e.g., PBPs ribosomes, DNA gyrase) Altered uptake or accumulation of drug (e.g., altered porins, membrane efflux pumps) Drug-modifying enzymes (e.g., - lactamases, aminoglycoside- modifying enzymes) Mechanisms of antimicrobial resistance

  3. N-acetylglucosamine N-acetylmuramic acid pentapeptide D-ala-D-ala Subunits for cell wall construction

  4. Second layer of cell wall cross-linked to the lower layer Cell Wall Assembly Layer of cell wall with cross links of 5 glycines (gray) A subunit is added to the growing chain Transpeptidase (PBP) forms a 5-glycine bridge between peptides

  5. Transpeptidase, or PBP (orange sunburst)is bound by beta-lactam antibiotic (light blue)and its activity is inhibited (turns gray)

  6. 5-glycine crosslinking bridges cannot form in the presence of a beta-lactam, and the cell wall is deformed and weakened

  7. Mechanisms of beta-lactam resistance • Drug-modifying enzymes (beta-lactamases) • Gram-positives(e.g., S. aureus) excrete the enzyme • Gram-negative (e.g., E. coli) retain the enzyme in the periplasm • Overexpression of cell wall synthetic enzymes • e.g., vancomycin-intermediate S. aureus (VISA) • Alteration of the PBPs so antibiotic cannot bind • e.g., S. pneumoniae, gonococcus • Exclusion from the site of cell wall synthesis • Porin mutations in the outer membrane of Gram-negative bacteria only (e.g., Ps. aeruginosa)

  8. Beta-lactamases Beta-lactamases (dark orange)bind to the antibiotics (light blue)and cleave the beta-lactam ring.The antibiotic is no longer able to inhibit the function of PBP (orange sunburst)

  9. Beta-lactamase activity

  10. Altered drug targets

  11. Vancomycin-intermediate S. aureus Production of excessive cell wall; the antibiotic cannot keep up MRSA VISA vancomycin MIC = 2 µg/ml vancomycin MIC =8 µg/ml

  12. MRSA VISA

  13. D-ala-D-ala V Mechanism of vancomycin action

  14. D-ala-D-lactate V Mechanism of vancomycin resistance Vancomycin is unable to bind to the D-ala-D-lactate structure

  15. June 2002: isolated from the catheter exit site in a chronic dialysis patient • The patient had received multiple courses of abx since April 2001; toe amputation in April 2002 --> MRSA bacteremia • VRSA also found at amputation stump wound (with VRE and Klebsiella); not in the patient’s nose • Vancomycin MIC >128mcg/ml!! (contains vanA) • Sensitive to trim/sulfa, chloro, tetracyclines, Synercid, linezolid

  16. MRSA and penicillin-resistant S. pneumoniae • These bacteria are both resistant because they have altered bacterial targets -- penicillin-binding proteins (PBPs or transpeptidases) • In MRSA, the altered PBP2 (mecA) gene is acquired by gene transfer from another bacterium. • In pneumococci, the alteration in PBP is generated by uptake of DNA released by dead oral streptococci and recombination at the pneumococcal pbp gene to create a new, chimeric protein that does not bind penicillin. • depicted on the next slide . . .

  17. DNA alpha-strep pbp S. pneumoniae transformation alpha-strep pbp S. pneumoniae chromosomal pbp; penicillin-sensitive Chimeric pbp (resistant to penicillin) Alpha-strep

  18. Altered porin channel prevents access of the antibiotic to the cell wall Beta-lactam (blue) enters through an outer membrane porin channel Outer membrane Cell wall (peptidoglycan) Inner membrane Cytoplasm Outer membrane permeability in Gram-negative bacteria Bacterium

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