Chem167_L18_Jun4_final

Drug resistant klebsiella traced to one paent caused a

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Unformatted text preview: • Allow bacteria to be resistant to penicillin • Transferable between bacterial strains (i.e. bacteria can acquire resistance) • Important w.r.t. Staphylococcus aureus infec#ons in hospitals • 80% Staph. infec#ons in hospitals were resistant to penicillin and other an#bacterial agents by 1960 • Mechanism of ac#on for lactamases is iden#cal to the mechanism of inhibi#on for the target enzyme •  But product is removed efficiently from the lactamase ac#ve site O O C H N H S R N C Me Me O CO2H H N H S R β- Lactamase HO2C HN Me Me CO2H Problem 2 - Sensi#vity to β- Lactamases Strategy • Use of steric shields • Block access of penicillin to the ac#ve site of the enzyme by introducing bulky groups to the side chain • Size of shield is crucial to inhibit reac#on of penicillins with β- lactamases, but not with the target transpep#dase enzyme O Bulky group C H N H H S Me R N Enzyme Me O CO2H Problem 2 - Sensi#vity to β- Lactamases Examples - Methicillin (Beechams - 1960) ortho groups important O MeO C H N H H S N OMe Me Me O CO2H • Methoxy groups block access to β- lactamases but not to transpep#dases • Binds less readily to transpep#dases compared to penicillin G • Lower ac#vity compared to Pen G against Pen G sensi#ve bacteria • Poor ac#vity vs. some streptococci • Inac#ve vs. Gram - ve bacteria • Poorer range of ac#vity • Ac#ve against some penicillin G resistant strains (e.g. Staphylococcus) • Acid sensi#ve since there is no electron- withdrawing group • Orally inac#ve and must be injected Methicillin- resistant Staphylococcus Aureus (MRSA) Staph bacteria that are resistant to beta- lactams Mostly skin infec#ons Hospitals Athletes Dorms/barracks/prisons/daycare fac...
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