Topic 8-1 Antibacterial Agents PDF
Preview Topic 8-1 Antibacterial Agents
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
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