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Paetzel, Mark; Danel, Franck; Castro, Liza de; Mosimann, S.C.; Page, Malcolm G. P.; Strynadka, N.C.J.

doi:10.1038/79688

Cited by 140 publications

(31 citation statements)

References 42 publications

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“…First, there is a strong incompatibility between the thiazole ring of the drug and the enzyme’s omega loop, particularly in the area of W167/L168. As first noted by Paetzel et al ., 44 most of the ESBL variants in the OXA-10 subfamily have mutations either in or near this loop. Indeed, mutation of the tryptophan or leucine has been shown to generate enzymes that confer strong ceftazidime resistance on Pseudomonas aeruginosa .…”

Section: Discussionmentioning

confidence: 99%

Structural Basis of Activity against Aztreonam and Extended Spectrum Cephalosporins for Two Carbapenem-Hydrolyzing Class D β-Lactamases from Acinetobacter baumannii

Mitchell¹,

Clasman²,

June³

et al. 2015

Biochemistry

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The carbapenem-hydrolyzing class D β-lactamases OXA-23 and OXA-24/40 have emerged world-wide as causative agents for β-lactam antibiotic resistance in Acinetobacter species. Many variants of these enzymes have appeared clinically, including OXA-160 and OXA-225, which both contain a P→S substitution at homologous positions in the OXA-24/40 and OXA-23 backgrounds respectively. We purified OXA-160 and OXA-225 and used steady-state kinetic analysis to compare the substrate profiles of these variants to their parental enzymes, OXA-24/40 and OXA-23. OXA-160 and OXA-225 possess greatly enhanced hydrolytic activities against aztreonam, ceftazidime, cefotaxime and ceftriaxone when compared to OXA-24/40 and OXA-23. These enhanced activities are the result of much lower Km values, suggesting that the P→S substitution enhances the binding affinity of these drugs. We have determined the structures of the acylated forms of OXA-160 (with ceftazidime and aztreonam) and OXA-225 (ceftazidime). These structures show that the R1 oxyimino side-chain of these drugs occupies a space near the β5-β6 loop and the omega loop of the enzymes. The P→S substitution found in OXA-160 and OXA-225 results in a deviation of the β5-β6 loop, relieving the steric clash with the R1 side-chain carboxypropyl group of aztreonam and ceftazidime. These results reveal worrying trends in the enhancement of substrate spectrum of class D β-lactamases, but may also provide a map for β-lactam improvement.

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Section: Discussionmentioning

confidence: 99%

Structural Basis of Activity against Aztreonam and Extended Spectrum Cephalosporins for Two Carbapenem-Hydrolyzing Class D β-Lactamases from Acinetobacter baumannii

Mitchell¹,

Clasman²,

June³

et al. 2015

Biochemistry

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“…Crystal structures of class D carbapenemases, OXA-23, OXA-24/40, OXA-48, OXA-58, and OXA-146 [103,104,105,106,107,108], and class D non-carbapenemases, OXA-1 from E. coli , OXA-10 from P. aeruginosa , and OXA-13 from P. aeruginosa [109,110,111], have been determined. The catalytic efficiencies ( K cat / K m ) of OXA-23 [104], OXA-24/40 [112], OXA-48 [113], and OXA-58 [114] for imipenem were 0.073, 0.015, 0.37, and 0.169 µM −1 ·S −1 , respectively.…”

Section: Non-metallo-carbapenemases: Zinc-independent Classes a Cmentioning

confidence: 99%

Structural Basis for Carbapenem-Hydrolyzing Mechanisms of Carbapenemases Conferring Antibiotic Resistance

Jeon

Lee

et al. 2015

IJMS

145

121

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Carbapenems (imipenem, meropenem, biapenem, ertapenem, and doripenem) are β-lactam antimicrobial agents. Because carbapenems have the broadest spectra among all β-lactams and are primarily used to treat infections by multi-resistant Gram-negative bacteria, the emergence and spread of carbapenemases became a major public health concern. Carbapenemases are the most versatile family of β-lactamases that are able to hydrolyze carbapenems and many other β-lactams. According to the dependency of divalent cations for enzyme activation, carbapenemases can be divided into metallo-carbapenemases (zinc-dependent class B) and non-metallo-carbapenemases (zinc-independent classes A, C, and D). Many studies have provided various carbapenemase structures. Here we present a comprehensive and systematic review of three-dimensional structures of carbapenemase-carbapenem complexes as well as those of carbapenemases. We update recent studies in understanding the enzymatic mechanism of each class of carbapenemase, and summarize structural insights about regions and residues that are important in acquiring the carbapenemase activity.

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“…The simplest scenario would be to have the proton transferred to the leaving group (the β-lactam nitrogen in acylation and the S67 alcohol in deacylation) via S115 11,36,37 . The positive charge of a second active-site lysine (K205) may encourage the role of S115 as an intermediary in a proton relay 10 . While S115 is almost always found within hydrogen bonding distance of S67, most structures do not place it close enough to hydrogen bond with either of the oxygen atoms of carboxy-K70.…”

Section: Active-site Chemistry and The Catalytic Mechanismmentioning

confidence: 99%

“…Extensive structural analysis of dimeric enzymes such as OXA-10, OXA-46 and OXA-48 show a similar mode of dimerization mediated by α9 and β4 9,10 . OXA-1 and OXA-24/40, which are members of distinct subfamilies in the class D group, are shown to be monomeric 8,11 .…”

Section: Introductionmentioning

confidence: 99%

Class D β-Lactamases: A Reappraisal after Five Decades

2013

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Conspectus Despite 70 years of clinical use, β-lactam antibiotics still remain at the forefront of antimicrobial chemotherapy. The major challenge to these life-saving therapeutics is the presence of bacterial enzymes (i.e., β-lactamases) that can hydrolyze the β-lactam bond and inactivate the antibiotic. These enzymes can be grouped into 4 classes (A-D). Among the most genetically diverse are the class D β-lactamases. In this class are β-lactamases that can inactivate the entire spectrum of β- lactam antibiotics (penicillins, cephalosporins, and carbapenems). Class D β-lactamases are mostly found in Gram-negative bacteria such as Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, and Acinetobacter baumannii. The active-sites of class D β-lactamases contain an unusual N-carboxylated lysine post-translational modification. A strongly hydrophobic active-site helps create the conditions that allow the lysine to combine with CO2, and the resulting carbamate is stabilized by a number of hydrogen bonds. The carboxy-lysine plays a symmetric role in the reaction, serving as a general base to activate the serine nucleophile in the acylation reaction, and the deacylating water in the second step. There are more than 250 class D β-lactamases described, and the full set of variants shows remarkable diversity with regard to substrate binding and turnover. Narrow-spectrum variants are most effective against the earliest generation penicillins and cephalosporins such as ampicillin and cephalothin. Extended-spectrum variants (also known as extended-spectrum β-lactamases, ESBLs) pose a more dangerous clinical threat as they possess a small number of substitutions that allow them to bind and hydrolyze later generation cephalosporins that contain bulkier side-chain constituents (eg. cefotaxime, ceftazidime, and cefepime). Mutations that permit this versatility seem to cluster in the area surrounding an active-site tryptophan resulting in a widened active-site to accommodate the oxyimino side-chains of these cephalosporins. More concerning are the class D β-lactamases that hydrolyze clinically-important carbapenem β-lactam drugs (e.g., imipenem). Whereas carbapenems irreversibly acylate and inhibit narrow- spectrum β-lactamases, class D carbapenemases are able to recruit and activate a deacylating water. The rotational orientation of the C6 hydroxyethyl group found on all carbapenem antibiotics likely plays a role in whether the deacylating water is effective or not. Inhibition of class D β-lactamases is a current challenge. Commercially available inhibitors that are active against other classes of β-lactamases are ineffective against class D enzymes. On the horizon are several compounds, consisting of both β-lactam derivatives and non-β-lactams, that have the potential of providing novel leads to design new mechanism-based inactivators that are effective against the class D enzymes. Several act synergistically when given in combination with a β-lactam antibiotic, and others show a unique mechanism of inhibition that is d...

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Untitled

Cited by 140 publications

References 42 publications

Structural Basis of Activity against Aztreonam and Extended Spectrum Cephalosporins for Two Carbapenem-Hydrolyzing Class D β-Lactamases from Acinetobacter baumannii

Structural Basis of Activity against Aztreonam and Extended Spectrum Cephalosporins for Two Carbapenem-Hydrolyzing Class D β-Lactamases from Acinetobacter baumannii

Structural Basis for Carbapenem-Hydrolyzing Mechanisms of Carbapenemases Conferring Antibiotic Resistance

Class D β-Lactamases: A Reappraisal after Five Decades

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