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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

Mechanisms of antimicrobial action directed against the bacterial cell wall and corresponding resistance mechanisms


Mechanisms of antimicrobial resistance

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


Subunits for cell wall construction

N-acetylglucosamine

N-acetylmuramic acid

pentapeptide

D-ala-D-ala

Subunits for cell wall construction


Cell wall assembly

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


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


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


Mechanisms of beta lactam resistance
Mechanisms of beta-lactam resistance of a beta-lactam, and the cell wall is deformed and weakened

  • 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)


Beta-lactamases of a beta-lactam, and the cell wall is deformed and weakened

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)


Beta lactamase activity
Beta-lactamase activity of a beta-lactam, and the cell wall is deformed and weakened


Altered drug targets

Altered drug targets of a beta-lactam, and the cell wall is deformed and weakened


Vancomycin intermediate s aureus
Vancomycin-intermediate of a beta-lactam, and the cell wall is deformed and weakenedS. aureus

Production of excessive cell wall; the antibiotic cannot keep up

MRSA

VISA

vancomycin MIC = 2 µg/ml

vancomycin MIC =8 µg/ml


MRSA of a beta-lactam, and the cell wall is deformed and weakened

VISA


Mechanism of vancomycin action

D-ala-D-ala of a beta-lactam, and the cell wall is deformed and weakened

V

Mechanism of vancomycin action


Mechanism of vancomycin resistance

D-ala- of a beta-lactam, and the cell wall is deformed and weakenedD-lactate

V

Mechanism of vancomycin resistance

Vancomycin is unable to bind to the D-ala-D-lactate structure


  • 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


Mrsa and penicillin resistant s pneumoniae
MRSA and penicillin-resistant dialysis patientS. 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 . . .


DNA dialysis patient

alpha-strep pbp

S. pneumoniae

transformation

alpha-strep pbp

S. pneumoniae chromosomal pbp; penicillin-sensitive

Chimeric pbp (resistant to penicillin)

Alpha-strep


Outer membrane permeability in gram negative bacteria

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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