Sandbox Reserved 994: Difference between revisions
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''Acinetobacter baumannii'' is a strain of bacteria which is resistant to a large number of β-lactams and produces three different types of β-lactamases. It was also involved in a nosocomial outbreak in Spain.<ref name = AB> Bou, German, Antonio Oliver, and Jesus Martinez-Beltran. "OXA-24, a Novel Class D β-Lactamase with Carbapenemase Activity in an ''Acinetobacter Baumannii'' Clinical Strain." Antimicrobial Agents and Chemotherapy 44, no. 6 (2000): 1556-561. Accessed February 19, 2015. http://aac.asm.org/content/44/6/1556.full</ref> It is dangerous in hospitals because its antibacterial resistance allows it to infect patients who are taking antibiotics. By taking antibiotics, they are clearing out their system and clearing the way for this bacteria to take over.<ref> Dijkshoorn, Lenie, Alexandr Nemec, and Harald Seifert. "An Increasing Threat in Hospitals: Multidrug-resistant ''Acinetobacter Baumannii.''" Nature Reviews Microbiology 5, No. 12 (2007): 939-51. Accessed February 19, 2015. http://www.nature.com/nrmicro/journal/v5/n12/full/nrmicro1789.html </ref> This strain of bacteria uses three different β-lactamases to protect itself from antibiotics, one of which is a newly discovered enzyme called OXA-24 β-lactamase. This enzyme is inhibited by chloride ions, tazobactam, sulbactam, and clavulanic acid; and specifically counteracts benzylpenicillin and cephaloridine.<ref name = AB /> | ''Acinetobacter baumannii'' is a strain of bacteria which is resistant to a large number of β-lactams and produces three different types of β-lactamases. It was also involved in a nosocomial outbreak in Spain.<ref name = AB> Bou, German, Antonio Oliver, and Jesus Martinez-Beltran. "OXA-24, a Novel Class D β-Lactamase with Carbapenemase Activity in an ''Acinetobacter Baumannii'' Clinical Strain." Antimicrobial Agents and Chemotherapy 44, no. 6 (2000): 1556-561. Accessed February 19, 2015. http://aac.asm.org/content/44/6/1556.full</ref> It is dangerous in hospitals because its antibacterial resistance allows it to infect patients who are taking antibiotics. By taking antibiotics, they are clearing out their system and clearing the way for this bacteria to take over.<ref> Dijkshoorn, Lenie, Alexandr Nemec, and Harald Seifert. "An Increasing Threat in Hospitals: Multidrug-resistant ''Acinetobacter Baumannii.''" Nature Reviews Microbiology 5, No. 12 (2007): 939-51. Accessed February 19, 2015. http://www.nature.com/nrmicro/journal/v5/n12/full/nrmicro1789.html </ref> This strain of bacteria uses three different β-lactamases to protect itself from antibiotics, one of which is a newly discovered enzyme called OXA-24 β-lactamase. This enzyme is inhibited by chloride ions, tazobactam, sulbactam, and clavulanic acid; and specifically counteracts benzylpenicillin and cephaloridine.<ref name = AB /> | ||
== Structure == | |||
OXA-24 is a monomeric protein with an active site composed of a short α-helix and a β-sheet. The active site of OXA-24 is characterized by a hydrophobic pocket, which is representative of Class D β-lactamases as a whole. The hydrophobic bridge contributes to the substrate specificity for carbapenems and is composed of an arrangement of the Tyr-112 and Met-223 side chains.<ref name="Santillana">Santillana, Elena et al. “Crystal Structure of the Carbapenemase OXA-24 Reveals Insights into the Mechanism of Carbapenem Hydrolysis.” Proceedings of the National Academy of Sciences of the United States of America 104.13 (2007): 5354–5359. PMC. Web. 25 Mar. 2015.</ref> <scene name='69/691536/Oxa24_bridge/1'>Bridge</scene> These residues block the active site and only allow a very specific binding configuration of antibiotics. The active site is overall positively charged and contains a sulfate ion along with other solvent molecules when no substrate is bound. The mechanism of attack is through the use of three catalytic residues: Serine-81, Carboxylated Lysine-84, and Serine-128. <scene name='69/691536/Catalytic_residues_oxa24/1'>Catalytic Residues</scene> The hydroxyl chain of Ser-128 conforms in the direction of the active-serine Ser-81, and contributes to the catalytic mechanism.<ref name="Santillana" /> | |||
== Bacterial Resistance == | == Bacterial Resistance == | ||
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Due to overperscription and misuse of antibiotics, bacteria have been able to develop resistance mechanisms. One of these resistance mechanisms is through the expression of β-lactamases, which have evolved as a seperate enzyme over millions of years from PBP.<ref>Meroueh, S.O; Minasov, G; Lee, W; Shoichet, B.K; Mobashery, S. Structural aspects for evolution of beta-lactamases from penicillin-binding proteins. J. Am. Chem Soc. (2003), 125, 9612-9618. </ref> β-lactamases act by hydrolyzing the β-lactam ring, which renders the antibiotic inactive before it has a chance to inhibit the transpeptidase enzymes.<ref>Neu, Harold. "The Crisis in Antibiotic Resistance." Science (1992) 257, 5073. ProQuest Medical Library: p. 1064-1072.</ref> β-lactamases are grouped into four different classes (A, B, C and D); all of which, with the exception of class B, use a serine based mechanism for destruction of β-lactams. Class B β-lactamases use zinc ions for hydrolysis. Class D was distinguished from other serine β-lactamases in the late 1980s, due to having an affinity for oxacillin as its substrate in addition to other antibiotics.<ref>doi: 10.1128/AAC.01009-09</ref> Even more concerning is that the class D β-lactamases, or OXAs, are not inhibited by current clinical β-lactamase inhibitors such as clavulanic acid. OXA-24, which has considerable carbapenemase activity, poses a dangerous clinical threat due to the absence of an effective inhibitor. | Due to overperscription and misuse of antibiotics, bacteria have been able to develop resistance mechanisms. One of these resistance mechanisms is through the expression of β-lactamases, which have evolved as a seperate enzyme over millions of years from PBP.<ref>Meroueh, S.O; Minasov, G; Lee, W; Shoichet, B.K; Mobashery, S. Structural aspects for evolution of beta-lactamases from penicillin-binding proteins. J. Am. Chem Soc. (2003), 125, 9612-9618. </ref> β-lactamases act by hydrolyzing the β-lactam ring, which renders the antibiotic inactive before it has a chance to inhibit the transpeptidase enzymes.<ref>Neu, Harold. "The Crisis in Antibiotic Resistance." Science (1992) 257, 5073. ProQuest Medical Library: p. 1064-1072.</ref> β-lactamases are grouped into four different classes (A, B, C and D); all of which, with the exception of class B, use a serine based mechanism for destruction of β-lactams. Class B β-lactamases use zinc ions for hydrolysis. Class D was distinguished from other serine β-lactamases in the late 1980s, due to having an affinity for oxacillin as its substrate in addition to other antibiotics.<ref>doi: 10.1128/AAC.01009-09</ref> Even more concerning is that the class D β-lactamases, or OXAs, are not inhibited by current clinical β-lactamase inhibitors such as clavulanic acid. OXA-24, which has considerable carbapenemase activity, poses a dangerous clinical threat due to the absence of an effective inhibitor. | ||
== Hydrolysis | == β-lactam Hydrolysis == | ||
[[Image:B-lactam hydrolysis3.png|800px|none|thumb|alt=text|β-lactam antibiotics (basic structure of a β-lactam is shown above) are hydrolyzed by β-lactamase enzymes, utilizing a covalent catalysis serine-based mechanism. The β-lactamase cleaves the amide bond of the four membered ring which renders the antibiotic inactive before it reaches its bacterial target, the transpeptidase enzymes.]] | [[Image:B-lactam hydrolysis3.png|800px|none|thumb|alt=text|β-lactam antibiotics (basic structure of a β-lactam is shown above) are hydrolyzed by β-lactamase enzymes, utilizing a covalent catalysis serine-based mechanism. The β-lactamase cleaves the amide bond of the four membered ring which renders the antibiotic inactive before it reaches its bacterial target, the transpeptidase enzymes.]] | ||
