Penecillins Case Study

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Penecillins were widely and unwisely used to treat serious infections for nearly 60 years due to their excellent efficacy, safety and tolerability profiles, so this led to the emergence of β lactamase which threatened the use of penecillins, because of that scientists started to look for β lactamase inhibitor. In 1976 scientists discovered the first β lactamase antagonists, generated from gram-positive bacteria, called olivanic acid. However because of its poor stability and poor ability to cross bacterial cells, scientists lost their interest in this natural product. After that scientists started to look for further β lactamase inhibitors and they ended up with 2 agents: calvulanic acid and thienamycin. Thienamycin was the first cabapenem…show more content…
Addition of carbon at (C-1) had major role in making the drug more potent, more stable for β lactamase and with broad spectrum of activity. Most carbapenems contain trans-1-hydroxyethyl substitution and 1- β -methyl group as an additional moiety.(1)(2) 2)trans-1-hydroxyethyl: Instead of the acylamino substituent on the β lactam ring, carbapenems contain trans-1-hydroxyethyl substituent. This side chain extend under the plane of β lactam ring. It plays a role in resistance to hydrolysis by β lactamase and its stereochemistry is critical for activity. Although carbapenems rapidly acylate the serine residue on β lactamases, the hydrolysis of the acylated enzyme is very slow because the trans-1-hydroxyethyl moiety displaces water that is necessary for hydrolysis at the active site. Therefore the enzyme become acylated and inactive. 3)1-B-methyl group : in order to overcome the inactivation of the drug through hydrolysis by mammalian hydrolase (dehydropeptidase-I), scientists discovered that addition of B-methyl group acts as a shield that protects the B lactam carbonyl group, so it decrease the hydrolysis by…show more content…
imipenem Meropenem and doripenem ); includes broad-spectrum carbapenem, with activity against non-fermentative Gram-negative bacilli, and have less sensitive to base hydrolysis in solution Imipenem have high affinity for PBPs and stability against β-lactamases .both drugs are suitable for nosocomial infections and coadministration with an inhibitor, cilastatin or betamipron ,was essential Group 3 includes carbapenem with clinical activity against MRS, and it is under development ( eg: pz-601). Carbapenem resistance All Carbapenem have resistance to Many nonfermenting Gram-negative bacteria (e.g., Pseudomonas spp., Acinetobacter spp., and Stenotrophomonas spp.), also the Enterobacteriaceae (e.g., Klebsiella spp., Escherichia coli, and Enterobacter spp.) as well as Gram-positive bacteria (e.g., Staphylococcus spp., Streptococcus spp., Enterococcus spp., and Nocardia spp.). Mechanisms of resistance to carbapenem such as production of β-lactamases, efflux pumps, and mutations that alter the expression and/or function of porins and PBPs. highly level of resistance result from Combinations of these mechanisms in certain bacterial species, include Klebsiella pneumoniae, P. aeruginosa, and A.

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