抗生素英文课件精品 Clinically Important β-Lactam Antibiotics案例实例.pptVIP

Beta-Lactam Antibiotics Clinically Important β-Lactam Antibiotics Medicinal Chemistry Presentation David McLeod Southern Methodist University Introduction β-Lactam antibiotics are the most widely produced and used antibacterial drugs in the world, and have been ever since their initial clinical trials in 1941. β-Lactams are divided into several classes based on their structure and function; and are often named by their origin, but all classes have a common β-Lactam ring structure. History 1928- Alexander Fleming discovers a mold which inhibits the growth of staphylococcus bacteria 1940- penicillin is isolated and tested on mice by researchers at Oxford 1941- penicillin mass produced by fermentation for use by US soldiers in WWII 1950’s- 6-APA is discovered and semi-synthetic penicillins are developed. 1960’s to today- novel β-lactams/ β-lactamase inhibitors are discovered and modified from the natural products of bacteria Target- Cell Wall Synthesis The bacterial cell wall is a cross linked polymer called peptidoglycan which allows a bacteria to maintain its shape despite the internal turgor pressure caused by osmotic pressure differences. If the peptidoglycan fails to crosslink the cell wall will lose its strength which results in cell lysis. All β-lactams disrupt the synthesis of the bacterial cell wall by interfering with the transpeptidase which catalyzes the cross linking process. Mechanism of β-Lactam Drugs The amide of the β-lactam ring is unusually reactive due to ring strain and a conformational arrangement which does not allow the lone pair of the nitrogen to interact with the double bond of the carbonyl. β-Lactams acylate the hydroxyl group on the serine residue of PBP active site in an irreversible manner. This reaction is further aided by the oxyanion hole, which stabilizes the tetrahedral intermediate and thereby reduces the transition state energy. Mechanism of β-Lactam Drugs The hydroxyl attacks the amide and forms a tetrahedral intermediate. Me