Chapter 8 Antibiotics
Wei-Min Chen, Prof.
Department of Medicinal Chemistry, JNU
Topics in This Class

Antibiotics

Definition, Classification, Development, and Action
mechanism of antibiotics.

β–Lactam antibiotics

Penicillins


Benzylpenicillin sodium, Amoxicillin, Oxacillin sodium
Semi-synthetic penicillins
Key issues: β–Lactam Antibiotics and Penicillins
Tough issues: Action mechanisms of antibiotics and Resistance
HISTORICAL BACKGROUND

Since 1940s, antibiotics have transformed
medicine; most infectious diseases can be
effectively controlled by the appropriate use of the
correct drugs.

plague(瘟疫)

typhus(伤寒)

cholera(霍乱)

tuberculosis(肺结核)
1928 Alexander Fleming, Inhibition of S.
aureus colonies by mold Penicillium notatum;
Discovered "miracle drug" Penicillin
Some Terms



Antibacterial Agents (Antimicrobial agents)
The drugs having bacteriostatic and bactericidal
activities for pathogenic microorganism，used
to treat pathogenic bacterial infections .
“bacteriostatic ’’ agents
They can inhibit bacterial cell growth only，but
do not actively kill the cells.
“bactericidal’’ agents
They can kill bacterial cells，but are nontoxic to
human cells .
Classification of Antimicrobial
agents


Antibiotics: (to be modeled after natural
products)
Synthetic antibacterial agents (Chapter 9)






Sulfonamides,（Antibacterial synergists）
Quinolone antibacterial agents
Nitrofurantoin antibacterial agents
Oxazolidiones
Antifungal agents
Taberculostatics
Definition of Antibiotics

Antibiotic (Literal definition): Against (anti-) life (biotic);

Antibiotic (Old definition): Chemical substance
produced by various species of microorganisms
that is capable, in low concentrations, of inhibiting
the growth of or killing other microorganisms
(Proposed by Waksman in 1942)
Definition of Antibiotics

Antibiotic (New definition): Substance
produced by a microorganism or a similar
product produced wholly (synthetic) or
partially (semi-synthetic) by chemical
synthesis and in low concentrations
inhibits
the
growth
of
or
kills
microorganisms
If a substance is classified as an
antibiotic

It is a product of metabolism (although it may be
duplicated or even have been anticipated by chemical
synthesis).

It is a synthetic product produced as a structural
analogue of a naturally occurring antibiotic.

It antagonizes the growth or survival of one or more
species of microorganisms.

It is effective in low concentrations.
Classification of Antibiotics
(According their structures)
1.β-Lactam antibiotics (β –内酰胺类)
2.Tetracyclines antibiotics (四环素类)
3. Aminoglycoside antibiotics (氨基糖甙类)
4. Macrolides antibiotics (大环内酯类)
5. Others (Chloramphenicol, 氯霉素)
Action Mechanisms of Antibiotic




Inhibition of Cell Wall Synthesis (most common
mechanism) →(β –Lactam)
Inhibition of Protein Synthesis (Translation)
(second largest class) →(Aminoglycosides,
Tetracyclines, Erythromycins, Chloramphenicol)
Alteration of Cell Membranes →(Amphotericin B)
Inhibition of Nucleic Acid Synthesis or action on
DNA and/or RNA →(Actinomycin, Rifampin)
Selective toxicity


Cell wall synthesis inhibitors: Human cell don't
have cell walls
Protein synthesis inhibitors:



Target 30S or 50S ribosomal structures that bacteria
have, that we don't have
Target bacterial protein synthesis that is occurring at a
much faster rate than in mammalian cells
Actively taken up into bacteria cells-not ours
1.β –Lactam Antibiotics
Penicillins
Cephalosporins
Monobactams
Carbapenems
β-Lactamase Inhibitors
1.β–Lactam Antibiotics
X H
X H
S
RCONH
RCONH
N
O
S
N
N
COOH
O
A
COOH
X= -H, -OCH3
X= -H, -OCH3
Penicillins
Cephalosporins
N
N
Penem
Carbapenem
O
S
O
O
O
Oxypenam
NH
O
Monobactam
1.β–Lactam Antibiotics
¦Á
O

¦Â
N
These all share a common β-lactam ring. The ring is
very strained and the bond between the carbonyl and
the nitrogen in the β-lactam ring is very labile and
hence makes the molecule reactive.
Three-dimensional structures
The R-group substitute of the penicillin nucleus can be
changed to give the molecule different antibacterial
properties. The two naturally occurring penicillins
from Penicillium notatum are Penicillin G, [Benzyl
penicillin, R = C6H6] and Penicillin V, [Phenoxymethyl
penicillin, R = CH2O(C6H6)]
O
R
X H
S
NH
N
O
H
COOH
The β-lactam structure is derived from two covalently
bonded amino acid residues; cysteine and valine. This
forms via a tripeptide intermediate where the third
amino acid is replaced by the variable R-group.
Mechanism of Action
O
O
O
R
N
N
O
O
N
S
R
N
O
D-Alanyl-D-Alanin
O
Penicillins
O
The Cell Wall Synthesis
MurNAc
L-Ala
D-Glu
m-DAP
D-Ala D-Ala
GlcNAc
D-Ala
m-DAP
D-Ala
D-Glu
L-Ala
MurNAc
GlcNAc
תëÄø
MurNAc
GlcNAc
L-Ala
D-Glu
m-DAP
D-Ala
transpeptidase
D-Ala
m-DAP
D-Ala
D-Glu
L-Ala
MurNAc
GlcNAc
Mechanism of action of -lactams
Mechanism of Action
Penicillin binds at the active site of the
transpeptidase enzyme that cross-links the
peptidoglycan strands. It does this by mimicking
the D-alanyl-D-alanine residues that would normally
bind to this site.
The labile β-lactam ring in penicillin reacts with a
serine residue in the transpeptidase. This reaction
is irreversible and so the growth of the bacterial cell
wall is inhibited.
Penicillin G and V are only active against Gram
Positive bacterial cells, which have an exposed
layer of peptidoglycan around the outside of the
cell wall, as shown below. Gram Negative
bacteria have a more complicated composition,
which Penicillin G and V can not destroy .
All β–lactam antibiotics owe their activity to
their ability to act as irreversible inhibitors of
the D-alanyl-D-alanine carboxypeptidase /
Transpeptidase. These enzymes are collectively
known as Penicllin-Binding Poteins, PBPs
R
OH
PBPs
N
O
H
NH3
COOH
glycopeptide
PBPs
peptidoglycan
strands
Cell Wall
-Lactam
Clinical use

β-lactam antibiotics are indicated for the
prophylaxis and treatment of bacterial infections
caused by susceptible organisms. At first, βlactam antibiotics were mainly active only against
Gram-positive bacteria, yet the recent
development of broad-spectrum β-lactam
antibiotics active against various Gram-negative
organisms has increased their usefulness.
The Penicillins
Benzylpenicillin Sodium
O
H H 4
5S
6
HN
3
7 N1
2
Bicyclo[3.2.0]heptane
O
H
ONa
O


Chemical name： （2S，5R，6R）-3，3-dimethyl-6-(2benzylacetamido)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane2-carboxylic acid
Penicillin G


Penicillins nucleus consists of the β–lactam ring fused
through a nitrogen atom and the adjacent tetrahedral
carbon atom to a 5-member thiazolidine ring. Both two
rings are strained.
In addition, the carbonyl group in benzylpenicillin can’t
form conjugate structure with the unshared electron pair of
nitrogen, so it’s not a normal amide. it can be easily
attacked by nucleophilic agent.
Structure and bonding of normal
amide
Degradation of penicillins
O
H H
N
H
O
S
N
H COOH
H + or HgCl2
O
O
N
H
OH
S
O
+
N
H
HN
H COOH
O
H
OH
O
ÇàùȩËá
Penaldic Acid
ÇàùËá
Penicilloic Acid
- CO2
O
O
N
H
Çàùȩ
Penilloaldehyde
Under pH4 and r.t. conditions
O
+
H
.. H H
S
N
H
N
..
O
H COOH
O
O
pH = 4
HO
O
N+
H
H
+
S
S
N
HN
COOH
Çàù¶þËá
Penillic Acid
H COOH
H+
O
O
N
H
Çàùȩ
Penilloaldehyde
O+
N
HS
OH
H NH2
Çàù°·
Penicillamine
Under base condition
O
O
H H
S
N
H
O
OH
-
H H
S
N
H
N
H COOH
-CO2
HN
OH
COOH
H
O
ÇàùËá
Penicilloic acid
O
H
N
H
S
HN
H
COOH
ÇàùàçßòËá
Penilloic acid
HgCl2
O
O
N
H
Çàùȩ
Penilloaldehyde
O+
HS
OH
H NH2
Çàù°·
Penicillamine
Benzylpenicillin react with amine or
alcohol
NH
RNH2
S
O
H
H
N
H H
O
O
OH
NHR
Amide of Penicilloic Acid
NH
S
O
H
H
O
N
O
H
ROH
OH
NH
S
O
H
H
O
N
H H
OR
Ester of Penicilloic Acid
O
OH
Resistance: Penicillin G is a typical example of
compounds that inhibit the action of DDtranspeptidases, but it is also a substrate for β–
lactamases.
Products
Natural Penicillins
The disadvantages of Penicillins
(Penicillin G)





Narrower in antibacterial spectrum, active
for G-P only, poor active for G-N.
Can not be oral administrated , just for
injection.
Allergic action (frequency : 0.7–10% ).
Susceptible to acid and Penicillinase.
Produces Penicllins-resistant bacteria.
Pencillinase-resistant penicillins
Oxacillin Sodium
O
H H
S
HN
N
O
N
O
.H2O
COONa

（2S，5R，6R）-3，3-Dimethyl-6-（5-methyl-3-phenyl4-isooxazoleformamide）-7-oxo-4-thia-1-azabicyclo[3.
2.0]heptane-2-carboxylic acid sodium monohydrate

Oxacillin was designed and discovered according to
bioisosterism from the Methicillin as lead compound.
Methicillin and Oxacillin
Aminopenicillins: the broader
antibacterial spectrum antibiotics
Amoxicillin
HO
O
H H
HN
H NH2
O

S
N
.3H2O
COOH
(2S,5R,6R)-3,3-Dimethyl-6-[(R)-(-)-2-amino-2-(4hydroxyphenyl)acetamido]-7-oxo-4-thia-1azabicyclo[3.2.0.]heptane-2-carboxylic acid trihydrate
Formation of polymer
HO
HO
O
H H
H NH 2
O
H NH2
O
N
O
COOH
HO
COOH
O
N
NH
HO
N
S
NH
H NH2
O
S
H H
HO
S
HN
COOH
NH
H
N
S
O
O
n
HN
COOH
NH
H
S
N
O
N
COOH
O
SAR of Penicillins
O
H
N
H
O
H
S
N
H COOH
The presence of a carboxy group is
a requirement for PBP recognition.
When esterition of it, it behaves a pro-drug
The bioavailability will be raisen.
SAR of Penicillins
O
H
N
H
O
H
S
N
H COOH
Three chiral centers are
requirement for Penicillins
bioactivity
SAR of Penicillins
Side chain can be replaced with different
R group to obtain different compounds
With broad antibacterial spectrum
O
H
N
H
O
H
S
N
H COOH
The synthetic routes of semi-synthetic
penicillins from 6-APA (6-Amino-Penicillanic
Acid)
H H
H2 N
S
N
O
H NH2
COOH
Cl
O
H NH2
R'
S
H H
R'
NH
N
O
O
RCOOH
R
O
H H
NH
N C N
O
O
HO
HO
O
O
S
R
H H
N
COOH
O
S
NH
N
COOH
O
COOH
The synthetic routes of semi-synthetic penicillins
--Key intermediate 6-Amino-Penicillanic Acid (6-APA)
O
H H
H H
S
HN
Penicillin G
S
H2N
N
N
O
Penicillin acylase
O
COOH
6-APA
COOH
Preparation of Salt of Penicillins
COONa
NH 2
H
NH
O
S
NH 2
H
OH
H
H
N
H
O
NH
O
O
S
H
H
N
O H
OH
O
ONa
O
ONa
N
HN
O
S
H
O
H
O
H
O
N
OH
CH3OH
N
HN
O
S
H
O
H
O
H
O
N
ONa
Brief summary




Typical drug
 Benzylpenicillin sodium, Amoxicillin
The structural characteristic of Pencillins
Semi-synthetic Penicillins
SAR of Penicillins
O
H
N
H
O
HO
H
S
N
H COOH
O
H H
HN
H NH2
O
S
N
.3H2O
COOH
Assignment:
 1.Read English textbook pp299-314
 2.Homework:


Experimental Medicinal Chemistry, exercises of
medicinal chemistry p84 Type A;
药物化学学习指导,第八章 8-2，8-3，8-8，8-46