The Beta Lactam Antibiotics

Intended Learning Outcomes

This lecture will enable you to:
Understand how Nice Yellow Medicine that
you took in childhood works
Understand what Nice Yellow Medicine is
and how it is made
Understand why you cant make Nice
Yellow Medicine in a practical class.

Bacterial targets for selective

inhibition
Cell wall
Cell membrane
DNA synthesis
Transcription
Protein synthesis in the
cytoplasm
(Other) metabolism

The bacterial cell wall

Bacteria are divided on the basis of cell
wall structure into Gram positive and
Gram negative
Gram positive
iodine

Gram negative

acetone

acetone

The cell membrane

Cell wall structure and function

The cell wall protects the cytoplasmic membrane
from rupture
Cell membrane is fragile
Osmotic pressure inside cell is high
Cell wall maintains shape of cell
Gram negative bacteria have an outer
membranelike structure.

Norcardiform bacteria
Cell walls of nocardiform bacteria
These include the mycobacteria such as M.
tuberculosis
Nocardiform bacteria are Gm +ve but are difficult to
stain.
Peptidoglycan is covalently linked to the
polysaccharide arabinogalactan.
Lipids are esterified to arabinogalactan and make up
60% of the dry cell weight.
Lipids confer resistance to staining and to antibiotics
and biocides.

Peptidoglycan
The major structural component of GM+v and
GM_ve cell walls consists of repeating
disaccharide unit of 2 different N-acetylated
aminosugars.
Short peptide chains are attached to alternate
aminosugars and these crosslink to one another
via peptide bonds.
Some bacteria have many sheets of
peptidoglycan and these are joined by the same
type of crosslink

The crosslinks between the polysaccharide

chains are species dependent
Example: E.coli peptidoglycan

N-acetylglucosamine
N-acetylmuramic acid
L-alanine
D-glutamic acid
Meso-diaminopimelic acid
D-alanine

Transpeptidation
Crosslinks are formed by a transpeptidation reaction, catalysed by a
membrae-bound transpeptidase.

Carboxypeptidase
One of a number of other enzymes in the
cell membrane that acts on cell wall
synthesis.

-Lactam Antibiotics
Penicillins c. 1940s
Cephalosporins c. 1960s
Carbapenems c. 1990s
ALL CONTAIN LACTAM RING

The Penicillins
Penicillins were discovered by Alexander Fleming in the late
1920s.
Staphylococcus lawn
Zone of inhibition
Fungal growth

Fleming prepared an antibacterial broth from the Penicillium

notatum fungus and discovered many of its properties.
Penicillin G was later purified from the broth and found to be
the active ingredient.

The Penicillins
H
N

Ph
O

Developed by Florey
and Chain as part of
the second world war
effort.

N
O

COO -

The main difficulty

was to cultivate the
fungus to produce
more penicillin.

Recommended reading: The Mould in Dr Floreys Coat

by Eric Lax.

Biosynthesis of -lactams
Origins

Valine
Cysteine
Structural mimicry of D-ala-D-ala ?

Phenylalanine

-lactam action with

Transpeptidase / Carboxypeptidase

Critical Parameters Affecting

-Lactam Utility
Activity and usefulness of the -lactams is determined
by:

Ability to penetrate the cell wall

Resistance to -lactamases
Affinity of various Penicillin Binding Proteins
Resistance to stomach acid
Formulation, pharmacokinetics, toxicology etc.

Semi-synthetic penicillins

The Penicillin Story

Penicillin G: The original
Acid labile therefore injection, sensitive to -lactamase
degradation
Ampicillin: Semisynthetic
Acid stable (oral), sensitive to -lactamase degradation
Amoxicillin: Semisynthetic
Resistant to class 1 -lactamase enzymes
Methicillin and flucloxacillin: Semisynthetic
Resistant to all -lactamases

Beta lactams - Penicillins

Penicillin G

Amoxycillin

Ampicillin

Methicillin

Beta-lactams - cephalosporins

The cephalosporin nucleus is

biosynthesized in a closely similar
way to the penicillin nucleus
First generation cephalosporins
are now seldom used
Second generation cephalosporins
have Gram negative activity and
are administered orally
Third generation cephalosporins
have good Gram negative activity,
are useful against very serious
illness and are injected.

Cephalosporins
Cefaclor second generation
Gram negative activity and
activity against Haemophilus

Ceftriaxone third generation

Given by intramuscular
injection, for serious
infection, often in
combination with a macrolide
or aminoglycoside

Other beta-lactams
Carbapenems
Very broad spectrum
Resistant to most
beta-lactamases
Monobactams
Just one so far
Active against Gram
negatives only

Other beta-lactams
Imipenem, an example
of a carbapenem. It
is rapidly deactivated
by the kidneys unless
administered with a
specific inhibitor,
cilastatin.
Aztreonam, the only
monobactam in use at
the moment.

-Lactams
Inhibit cell wall synthesis
Combine the specificity of natural products
with the versatility of laboratory-based
drugs and are incredibly successful as a
result.
Have a heroic and inspiring history that
has informed the development of other
drugs.