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cell lysis from the high osmotic pressure of the host cell), that
covalently bond to PBP yielding stable, enzymatically
inactive, acyl–enzyme complexes.
RESISTANCE
4 membered ring
PENICILLINS
CLASSES OF β-LACTAMASES
Nucleus (red box): 6-aminopenicillanic acid A Extended spectrum β-lactamases that degrade
Responsible for the biological activity penicillins, some cephalosporins, & some carbapenems
Hydrolysis of the β-lactam ring by bacterial β- B Zinc dependent enzymes that destroy all β-lactams,
lactamases yields penicilloic acid (no antibacterial except aztreonam
activity) C β-lactamases active against cephalosporins
Substituent: secondary amino group (blue box) D Cloxacillin-degrading enzymes
Determine the pharmacologic & antibacterial
properties
Modification of target PBPs
High-molecular weight PBPs that have decreased
MECHANISM OF ACTION
affinity for the antibiotics
Basis of methicillin resistance in staphylococci & of
INHIBITS THE TRANSPEPTIDATION REACTION OF
penicillin resistance in pneumococci & most resistant
THE PEPTIDOGLYCAN SYNTHESIS
enterococci (produce PBPs that have low affinity to
beta-lactams)
Not inhibited except at relatively high, often
clinically unachievable, drug concentrations
Impaired penetration of drug to target PBPs
Occurs only in Gram-negative species due to its
impermeable outer membrane of their cell wall
Poor penetration alone is usually not sufficient to
confer resistance, but can become important in the
presence of a β-lactamase (even a relatively inefficient
one)
Beta-lactam antibiotics cross the outer membrane via
porins (protein channels), which enables hydrophilic
antibiotics to pass through the outer membrane of Gram
negative organisms
P.aeruginosa: (-) porins
Antibiotic efflux
Gram negative organisms can produce efflux
pumps, cytoplasmic & periplasmic protein components
that efficiently transport some β-lactam antibiotics from
the periplasm back across the cell wall outer membrane
Important mechanism of resistance:
Pseudomonas aeruginosa
Transpeptidase reaction (blue box) Escherichia coli
Neisseria gonorrhea
Beta lactam antibiotics are structural analogs of the D-alanyl-
D-alanine substrate of Penicillin Binding Proteins (an
enzyme that catalyzes the cross linking of 2 peptidoglycan
GENERAL CLASSIFICATION
Penicillin (natural)
Examples:
Penicillin G (benzylpenicillin)
Penicillin V (phenoxymethyl derivative)
Coverage:
Gram positive organisms
Gram negative cocci
Gram negative rods (little activity)
Non-β-lactamase-producing anaerobes
(+) Hydrolysis
Antistaphylococcal Penicillin
Examples:
Isoxazolyl penicillin (Oxacillin, Dicloxacillin, &
Cloxacillin)
Methicillin
Nafcillin
Coverage:
Staphylococci
Streptococci
(-) Hydrolysis by staphylococcal β-lactamase
Extended-spectrum Penicillin
Examples: Ampicillin, Amoxicillin, & Piperacillin
Coverage:
Gram positive organisms
Gram negative cocci
Gram negative rods (improved activity over
Penicillins)
Non-β-lactamase-producing anaerobes
(+) Hydrolysis (relative)
NATURAL PENICILLINS
Pharmacokinetics
Administration
Penicillin V is acid stable and therefore is better
absorbed from the GI tract
Penicillin G is acid labile and therefore IM or IV
route of administration is preferred
How do we prolong
Distribution
Excretion
Therapeutic Uses