Topic 8-1 Antibacterial Agents

54 Pages·2009·1.17 MB·English

by  Chem 150-2008

Topic 8-1 Antibacterial Agents
β-Lactam antibiotics-Chapter 16
Patrick
PPEENNIICCIILLLLIINNSS
O
H
C N H H
S
Me
R
N
Me
O
CO H
2
IINNTTRROODDUUCCTTIIOONN
• Antibacterial agents which inhibit bacterial cell wall synthesis
• Discovered by Fleming from a fungal colony (1928)
• Shown to be non toxic and antibacterial
• Isolated and purified by Florey and Chain (1938)
• First successful clinical trial (1941)
• Produced by large scale fermentation (1944)
• Structure established by X-Ray crystallography (1945)
• Full synthesis developed by Sheehan (1957)
• Isolation of 6-APA by Beechams (1958-60)
- development of semi-synthetic penicillins
• Discovery of clavulanic acid and β-lactamase inhibitors
SSTTRRUUCCTTUURREE
RR ==
O
H H H
CH
2
C N
S Me
BBeennzzyyll ppeenniicciilllliinn ((PPeenn GG)) R 66--AAmmiinnooppeenniicciillllaanniicc aacciidd
((66--AAPPAA))
N
RR == Me
AAccyyll ssiiddee
O
cchhaaiinn
O CH
2 CO H
2 TThhiiaazzoolliiddiinnee
rriinngg
PPhheennooxxyymmeetthhyyll ppeenniicciilllliinn ((PPeenn VV)) ββ--LLaaccttaamm
rriinngg
Side chain varies depending on carboxylic acid present in fermentation medium
CH CO H Penicillin G
2 2
present in corn steep liquor
OCH2 CO2H Penicillin V
(first orally active penicillin)
SShhaappee ooff PPeenniicciilllliinn GG
O
Me
C
H
R NH
S
Me
N
O
H H CO2H
..
FFoollddeedd ‘‘eennvveellooppee’’ sshhaappee
BBiioossyynntthheessiiss ooff PPeenniicciilllliinnss
O
H
C N
S Me
R
N
Me
O
CO H
2
CCYYSS VVAALL
PPrrooppeerrttiieess ooff PPeenniicciilllliinn GG
• Active vs. Gram + bacilli and some Gram - cocci
• Non toxic
• Limited range of activity
• Not orally active - must be injected
• Sensitive to β-lactamases
(enzymes which hydrolyse the β-lactam ring)
• Some patients are allergic
• Inactive vs. Staphylococci
DDrruugg DDeevveellooppmmeenntt
AAiimmss
• To increase chemical stability for oral administration
• To increase resistance to β-lactamases
• To increase the range of activity
SSAARR
Amide essential
Cis Stereochemistry essential
O
H
C N H H
S
Me
R
N
Me
O
Carboxylic acid essential
CO H
!"Lactam essential 2
CCoonncclluussiioonnss
Bicyclic system essential
• Amide and carboxylic acid are involved in binding
• Carboxylic acid binds as the carboxylate ion
• Mechanism of action involves the β-lactam ring
• Activity related to β-lactam ring strain
(subject to stability factors)
• Bicyclic system increases β-lactam ring strain
• Not much variation in structure is possible
• Variations are limited to the side chain (R)
MMeecchhaanniissmm ooff aaccttiioonn
• Penicillins inhibit a bacterial enzyme called the transpeptidase
enzyme which is involved in the synthesis of the bacterial cell wall
• The β-lactam ring is involved in the mechanism of inhibition
• Penicillin becomes covalently linked to the enzyme’s active site
leading to irreversible inhibition
O O O
H H H H H H H H H
C N C N C N
S Me S Me S Me
R R R
Enz-Nu
O C
Nu N Me -H N Me HN Me
Nu-Enz
O O
Enz CO2H H CO2H CO2H
CCoovvaalleenntt bboonndd ffoorrmmeedd
ttoo ttrraannssppeeppttiiddaassee eennzzyymmee
OH
IIrrrreevveerrssiibbllee iinnhhiibbiittiioonn
Szer
MMeecchhaanniissmm ooff aaccttiioonn -- bbaacctteerriiaall cceellll wwaallll ssyynntthheessiiss
NAM NAG NAM NAG NAM
L-Ala NAM NALG-Ala NAM NALG-Ala NAM
D-Glu D-Glu D-Glu
L-Ala L-Ala L-Ala
NAM NAG NAM NAG NAM
L-Lys L-Lys L-Lys
D-Glu D-Glu D-Glu
L-Ala L-Ala L-Ala
L-Lys L-Lys L-Lys
D-Glu D-Glu D-Glu
L-Lys L-Lys L-Lys
Bond formation
inhibited by
penicillin