BETA LACTAM COMPOUNDS
cell lysis from the high osmotic pressure of the host cell), that
4 membered ring
PENICILLINS
 Nucleus (red box): 6-aminopenicillanic acid
 Responsible for the biological activity
 Hydrolysis of the β-lactam ring by bacterial β-
lactamases yields penicilloic acid (no antibacterial
activity)
 Substituent: secondary amino group (blue box)
 Determine the pharmacologic & antibacterial
properties
MECHANISM OF ACTION
INHIBITS THE TRANSPEPTIDATION REACTION OF
THE PEPTIDOGLYCAN SYNTHESIS
Transpeptidase reaction (blue box)
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
units essential for maintaining cell integrity & prevention of
covalently bond to PBP yielding stable, enzymatically
inactive, acyl–enzyme complexes.
RESISTANCE
 Inactivation of antibiotic by β-lactamase (most common)
 β-lactamase: enzymes produced by bacteria that
break open the beta-lactam ring by hydrolysis
CLASSES OF β-LACTAMASES
A Extended spectrum β-lactamases that degrade
penicillins, some cephalosporins, & some carbapenems
B Zinc dependent enzymes that destroy all β-lactams,
except aztreonam
C β-lactamases active against cephalosporins
D Cloxacillin-degrading enzymes
 Modification of target PBPs
 High-molecular weight PBPs that have decreased
affinity for the antibiotics
 Basis of methicillin resistance in staphylococci & of
penicillin resistance in pneumococci & most resistant
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
 Escherichia coli
 Neisseria gonorrhea
 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