Invanz (Ertapenem)
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| + | <StructureSection load='InvanzStick.pdb' size='340' side='right' caption='Structure of Invanz and its crystallized complexes that characterize its effective action against a variety of difficult to treat bacteria' scene=''> | ||
Invanz (Ertapenem) is a 1-beta-methyl carbapenem antibiotic that is designed to treat multi drug resistant bacterial infections such as intra-abdominal infections, skin and skin suture infections, community-acquired pneumonia, complicated urinary tract infections including pyelonephritis, acute pelvic infections, and can be used as a prophylactic measure prior to colorectal surgery. Invanz is an injectable antibiotic, which can be administered intramuscularly. It is generally known to be an antibiotic to treat mostly life-threatening infections and is used sparingly <ref>Merck, Sharp, and Dohme Corporation. Highlight of Prescribing Information: Invanz. http://www.merck.com/product/usa/pi_circulars/i/invanz/invanz_pi.pdf (accessed November, 12 2016)</ref><ref name="merck">...</ref>. | Invanz (Ertapenem) is a 1-beta-methyl carbapenem antibiotic that is designed to treat multi drug resistant bacterial infections such as intra-abdominal infections, skin and skin suture infections, community-acquired pneumonia, complicated urinary tract infections including pyelonephritis, acute pelvic infections, and can be used as a prophylactic measure prior to colorectal surgery. Invanz is an injectable antibiotic, which can be administered intramuscularly. It is generally known to be an antibiotic to treat mostly life-threatening infections and is used sparingly <ref>Merck, Sharp, and Dohme Corporation. Highlight of Prescribing Information: Invanz. http://www.merck.com/product/usa/pi_circulars/i/invanz/invanz_pi.pdf (accessed November, 12 2016)</ref><ref name="merck">...</ref>. | ||
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| - | <Structure load='InvanzStick.pdb' size='350' frame='true' align='right' caption='Structure of Invanz and its crystallized complexes that characterize its effective action against a variety of difficult to treat bacteria' scene='' /> | ||
== Function == | == Function == | ||
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== Structural highlights == | == Structural highlights == | ||
| - | <scene name='74/746003/Invanz_with_features/1'>Invanz</scene> is a carbapenem which is a beta-lactam antibiotic (contains a beta lactam ring) that has antimicrobial action via inhibition of cell wall synthesis. This class of antibiotics is known for its broad spectrum of activity, and its structure allows it to bind penicillin binding proteins (PBPs) to inhibit bacterial cell wall synthesis in a variety of bacterial types <ref>PMID: 17488146</ref><ref name="Invanz1">...</ref>. Antibiotic resistance to carbapenems largely results from ability of the bacterial species to secrete beta-lactamase enzymes that prevent the antimicrobial from accomplishing its job. Beta-lactamases work by attacking and cleaving the beta-lactam ring of antibiotics before the antibiotic reaches its target such as the penicillin binding proteins <ref>PMID: 25485972</ref>. Invanz has resistance to many beta-lactamases since it has a <scene name='74/746003/Invanz_with_features/1'>trans-1-hydroxyethyl group</scene> (shown in pink) that confers resistance of the antibiotic to degradation by most beta-lactamases <ref>PMID: 15150178 </ref> <ref name="hammond">...</ref>. The <scene name='74/746003/Invanz_with_features/1'>beta-lactam ring</scene> (shown in purple) is a four-membered, nitrogen-containing ring that binds to PBPs, thus making them unable to continue bacterial cell wall synthesis. PBPs are enzymes found in the cell membrane that aid in cross-linking of peptidoglycan during cell wall synthesis <ref>PMID: 18266856</ref>. By inactivating PBPs and inhibiting cell wall synthesis, bacterial cell death will occur since the bacterial cells will lyse due to osmotic pressure <ref>Page, M.L. The mechanisms of reactions of beta lactam antibiotics. Accounts of Chemical Research, 1984, 17(4), 144-151 DOI: 10.1021/ar00100a005</ref>. There are various crystal structures of Invanz that help to elucidate its mechanism of action and effectiveness against some species of bacteria that are able to resist inhibition by other classes of antibiotics. The <scene name='74/746003/4qu3/1'>GES-2 Ertapenem Acyl-Enzyme Complex</scene> is a crystallized structure of Invanz bound to the GES-2 beta-lactamase in ''Pseudomonas aeruginosa''. The GES enzymes are the Guina Extended Spectrum beta-lactamases that help some bacteria resist attack of antibiotics <ref>PMID: 15225858</ref>. This crystal structure complex is important for illustrating the acylation event between the GES-2 enzyme and the Ertapenem. While Ertapenem is a broad spectrum antibtiotic, it has reduced efficacy in inhibiting ''Pseudomonas aeruginosa''. In this study, the kinetic activity of GES-1, GES-2, and GES-5 beta-lactamases were examined in order to better understand how these enzymes could confer resistance to carbapenems such as Invanz. In these types of beta-lactamases, a catalytic Serine at position 70 attacks the β-lactam ring of the antibiotic to form an acyl-enzyme intermediate. The Glu-166 acts as a general base to activate a water molecule for deacylation of the enzyme, and the Cys-69 and Cys-238 amino acid residues form a disulfide bond thought to be important for the stability and carbapenemase activity of the beta-lactamase enzyme. This study concluded that GES-1 is the weakest beta-lactamase in conferring resistance to carbapenem antibiotics, while GES-5 is the strongest beta-lactamase and GES-2 is intermediate in its resistance. The deacylating water molecule is retained in the active site of GES-2 due primarily to the presence of an asparagine at position 170, and this structural difference in the GES-2 active site accounts for the tightly bound deacylating water molecule. The hydrogen bonding between the acyl-enzyme complex and this water molecule weakens the GES-2 beta-lactamase’s activation for deacylation. Consequently, this deacylation step is less efficient in GES-2 when compared to GES-5, and thus the carbapenem such as Invanz is able to escape hydrolysis by some but not all the beta-lactamases within ''P. aeruginosa'' <ref>PMID: 18922024</ref>. The <scene name='74/746003/3zgp/1'>NMR structure of the catalytic domain from Enterococcus faecium l,d-transpeptidase acylated by ertapenem</scene> shows was used to better characterize the mechanism of action of by carbapenem antibiotics. PBPs vital for peptidoglycan synthesis are replaced by l,d-transpeptidases (ltds) in an ampicillin-resistant strain of ''E. faecium'' and in ''M. tuberculosis''. This structure shows that bacterial strains such as ''E. faecium'' and ''M. tuberculosis'' are successfully inhibited by ertepenem through acylation of the ltd. Specifically, the beta-lactam ring of the ertapenem acylates the nucleophilic serine that normally catalyzes the transpeptidation reaction during cross-linking of the bacterial cell wall. | + | <scene name='74/746003/Invanz_with_features/1'>Invanz</scene> is a carbapenem which is a beta-lactam antibiotic (contains a beta lactam ring) that has antimicrobial action via inhibition of cell wall synthesis. This class of antibiotics is known for its broad spectrum of activity, and its structure allows it to bind penicillin binding proteins (PBPs) to inhibit bacterial cell wall synthesis in a variety of bacterial types <ref>PMID: 17488146</ref><ref name="Invanz1">...</ref>. Antibiotic resistance to carbapenems largely results from ability of the bacterial species to secrete beta-lactamase enzymes that prevent the antimicrobial from accomplishing its job. Beta-lactamases work by attacking and cleaving the beta-lactam ring of antibiotics before the antibiotic reaches its target such as the penicillin binding proteins <ref>PMID: 25485972</ref>. Invanz has resistance to many beta-lactamases since it has a <scene name='74/746003/Invanz_with_features/1'>trans-1-hydroxyethyl group</scene> (shown in pink) that confers resistance of the antibiotic to degradation by most beta-lactamases <ref>PMID: 15150178 </ref> <ref name="hammond">...</ref>. The <scene name='74/746003/Invanz_with_features/1'>beta-lactam ring</scene> (shown in purple) is a four-membered, nitrogen-containing ring that binds to PBPs, thus making them unable to continue bacterial cell wall synthesis. PBPs are enzymes found in the cell membrane that aid in cross-linking of peptidoglycan during cell wall synthesis <ref>PMID: 18266856</ref>. By inactivating PBPs and inhibiting cell wall synthesis, bacterial cell death will occur since the bacterial cells will lyse due to osmotic pressure <ref>Page, M.L. The mechanisms of reactions of beta lactam antibiotics. Accounts of Chemical Research, 1984, 17(4), 144-151 DOI: 10.1021/ar00100a005</ref>. There are various crystal structures of Invanz that help to elucidate its mechanism of action and effectiveness against some species of bacteria that are able to resist inhibition by other classes of antibiotics. The <scene name='74/746003/4qu3/1'>GES-2 Ertapenem Acyl-Enzyme Complex</scene> is a crystallized structure of Invanz bound to the GES-2 beta-lactamase in ''Pseudomonas aeruginosa''. The GES enzymes are the Guina Extended Spectrum beta-lactamases that help some bacteria resist attack of antibiotics <ref>PMID: 15225858</ref>. This crystal structure complex is important for illustrating the acylation event between the GES-2 enzyme and the Ertapenem. While Ertapenem is a broad spectrum antibtiotic, it has reduced efficacy in inhibiting ''Pseudomonas aeruginosa''. In this study, the kinetic activity of GES-1, GES-2, and GES-5 beta-lactamases were examined in order to better understand how these enzymes could confer resistance to carbapenems such as Invanz. In these types of beta-lactamases, a catalytic Serine at position 70 attacks the β-lactam ring of the antibiotic to form an acyl-enzyme intermediate. The Glu-166 acts as a general base to activate a water molecule for deacylation of the enzyme, and the Cys-69 and Cys-238 amino acid residues form a disulfide bond thought to be important for the stability and carbapenemase activity of the beta-lactamase enzyme. This study concluded that GES-1 is the weakest beta-lactamase in conferring resistance to carbapenem antibiotics, while GES-5 is the strongest beta-lactamase and GES-2 is intermediate in its resistance. The deacylating water molecule is retained in the active site of GES-2 due primarily to the presence of an asparagine at position 170, and this structural difference in the GES-2 active site accounts for the tightly bound deacylating water molecule. The hydrogen bonding between the acyl-enzyme complex and this water molecule weakens the GES-2 beta-lactamase’s activation for deacylation. Consequently, this deacylation step is less efficient in GES-2 when compared to GES-5, and thus the carbapenem such as Invanz is able to escape hydrolysis by some but not all the beta-lactamases within ''P. aeruginosa'' <ref>PMID: 18922024</ref>. The <scene name='74/746003/3zgp/1'>NMR structure of the catalytic domain from Enterococcus faecium l,d-transpeptidase acylated by ertapenem</scene> shows was used to better characterize the mechanism of action of by carbapenem antibiotics. PBPs vital for peptidoglycan synthesis are replaced by l,d-transpeptidases (ltds) in an ampicillin-resistant strain of ''E. faecium'' and in ''M. tuberculosis''. This structure shows that bacterial strains such as ''E. faecium'' and ''M. tuberculosis'' are successfully inhibited by ertepenem through acylation of the ltd which prevents the ltd from continuing further cell wall synthesis.Specifically, the beta-lactam ring of the ertapenem acylates the nucleophilic serine that normally catalyzes the transpeptidation reaction during cross-linking of the bacterial cell wall. Ldts are inactivated by β–lactam antibiotics, the carbapenems, via formation of a thioester bond with the active–site cysteine <ref>PMID: 23574509</ref>. The <scene name='74/746003/3m6b/1'>crystal structure of the pre-isomerized ertapenem covalent adduct with the M. tuberculosis beta-lactamase </scene> and the <scene name='74/746003/3m6h/1'>crystal structure of the post-isomerized ertapenem covalent adduct with the ''M. tuberculosis'' beta-lactamase </scene> are structures from a publication that attempted to netter characterize the efficacy of beta-lactam antibiotics such as Invanz in treating ''M. tuberculosis''. Beta-lactam antibiotics are not used often to treat ''M. tuberculosis'' since the BlaC enzyme (a beta-lactamase enzyme found in M. tuberculosis) has shown resistance to antibiotics such as Invanz. Like other beta-lactamases, BlaC catalyzes the opening of the β-lactam ring through nucleophilic attack via an active site serine that causes formation of the acylenzyme, followed by the hydrolysis of the ester bond to open the beta-lactam ring and inactive the antibiotic <ref>PMID: 23574509</ref>. |
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013547/figure/F4/ Ltd Acylation by Ertapenem Mechanism] | [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013547/figure/F4/ Ltd Acylation by Ertapenem Mechanism] | ||
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