Clinical Variants of the Native Class D β-Lactamase of Acinetobacter baumannii Pose an Emerging Threat through Increased Hydrolytic Activity against Carbapenems

Schroder, Emma C.; Klamer, Zachary; Saral, A.; Sugg, Kyle A.; June, Cynthia M.; Wymore, Troy; Szarecka, Agnieszka; Leonard, David A.

doi:10.1128/aac.01277-16

Cited by 19 publications

(22 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While cephalosporins and monobactams are not currently used against A. baumannii , novel agents such as the cephalosporin cefiderocol and monobactam BAL30072 show great potential against carbapenem-resistant strains of that species [42–44]. Enhanced activity against advanced generation cephalosporins and aztreonam has now been observed for at least five unique variants of the OXA-23, OXA-24/40 and OXA-51/66 subfamilies of class D β-lactamases [9, 10, 20, 21]. These variants all achieve that enhanced activity with just 1–3 substitutions (or in one case, a single amino acid duplication) compared to their parental enzymes.…”

Section: Discussionmentioning

confidence: 99%

“…A large number of clinical variants of OXA-23, OXA-24/40 and OXA-51/66 have been identified with greatly enhanced substrate specificity stretching across all four main classes of β-lactam drugs (penicillins, cephalosporins, carbapenems and monobactams) [9, 10, 16, 20, 21]. Substitutions that affect the orientation of Ile129 in OXA-51/66 (I129L, P130Q, L167V) have been shown to decrease the K m values for carbapenems [9, 16, 21].…”

Section: Introductionmentioning

confidence: 99%

“…Substitutions that affect the orientation of Ile129 in OXA-51/66 (I129L, P130Q, L167V) have been shown to decrease the K m values for carbapenems [9, 16, 21]. Alterations in the β6β7 loop in all three subfamilies leads to a greatly expanded active site and reduced K m values for late-generation cephalosporins and the monobactam aztreonam [10, 20–22].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Multiple substitutions lead to increased loop flexibility and expanded specificity in Acinetobacter baumannii carbapenemase OXA-239

Harper

June

Taracila

et al. 2018

Biochemical Journal

Self Cite

View full text Add to dashboard Cite

OXA-239 is a class D carbapenemase isolated from an Acinetobacter baumannii strain found in Mexico. This enzyme is a variant of OXA-23 with three amino acid substitutions in or near the active site. These substitutions cause OXA-239 to hydrolyze late-generation cephalosporins and the monobactam aztreonam with greater efficiency than OXA-23. OXA-239 activity against the carbapenems doripenem and imipenem is reduced approximately 3-fold and 20-fold respectively. Further analysis demonstrated that two of the substitutions (P225S and D222N) are largely responsible for the observed alteration of kinetic parameters, while the third (S109L) may serve to stabilize the protein. Structures of OXA-239 with cefotaxime, doripenem and imipenem bound as acyl-intermediates were determined. These structures reveal that OXA-239 has increased flexibility in a loop that contains P225S and D222N. When carbapenems are bound, the conformation of this loop is essentially identical to that observed previously for OXA-23, with a narrow active site that makes extensive contacts to the ligand. When cefotaxime is bound, the loop can adopt a different conformation that widens the active site to allow binding of that bulky drug. This alternate conformation is made possible by P225S and further stabilized by D222N. Taken together, these results suggest that the three substitutions were selected to expand the substrate specificity profile of OXA-23 to cephalosporins and monobactams. The loss of activity against imipenem, however, suggests that there may be limits to the plasticity of class D enzymes with regard to evolving active sites that can effectively bind multiple classes of β-lactam drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Multiple substitutions lead to increased loop flexibility and expanded specificity in Acinetobacter baumannii carbapenemase OXA-239

Harper

June

Taracila

et al. 2018

Biochemical Journal

Self Cite

View full text Add to dashboard Cite

show abstract

“…Of considerable interest are those substitutions that occur in or near the active site, and those that have occurred independently multiple times. W222G and W222L have appeared in the context of OXA‐66, and the W222L mutation has been shown to lead to greater affinity for carbapenems . One of the most common substitutions is L167V, which has arisen in many different subtypes of OXA‐51‐like enzymes including OXA‐51 (yielding OXA‐219), OXA‐66 (OXA‐82), OXA‐69 (OXA‐107), and OXA‐71 (OXA‐113) .…”

Section: Introductionmentioning

confidence: 99%

The structure of a doripenem‐bound OXA‐51 class D β‐lactamase variant with enhanced carbapenemase activity

et al. 2016

Self Cite

View full text Add to dashboard Cite

OXA-51 is a class D β-lactamase that is thought to be the native carbapenemase of Acinetobacter baumannii. Many variants of OXA-51 containing active site substitutions have been identified from A. baumannii isolates, and some of these substitutions increase hydrolytic activity toward carbapenem antibiotics. We have determined the high-resolution structures of apo OXA-51 and OXA-51 with one such substitution (I129L) with the carbapenem doripenem trapped in the active site as an acyl-intermediate. The structure shows that acyl-doripenem adopts an orientation very similar to carbapenem ligands observed in the active site of OXA-24/40 (doripenem) and OXA-23 (meropenem). In the OXA-51 variant/doripenem complex, the indole ring of W222 is oriented away from the doripenem binding site, thereby eliminating a clash that is predicted to occur in wildtype OXA-51. Similarly, in the OXA-51 variant complex, L129 adopts a different rotamer compared to I129 in wildtype OXA-51. This alternative position moves its side chain away from the hydroxyethyl moiety of doripenem and relieves another potential clash between the enzyme and carbapenem substrates. Molecular dynamics simulations of OXA-51 and OXA-51 I129L demonstrate that compared to isoleucine, a leucine at this position greatly favors a rotamer that accommodates the ligand. These results provide a molecular justification for how this substitution generates enhanced binding affinity for carbapenems, and therefore helps explain the prevalence of this substitution in clinical OXA-51 variants.

show abstract

“…However, the Acinetobacter isolates carrying the ISAba1-bla OXA-51 -like genetic structure exhibit carbapenem MICs ranging from 1 to Ն64 mg/liter. A possible explanation for this phenomenon is that clinical variants of OXA-51 enzymes exhibit different hydrolytic activities against carbapenems (16,17). In addition, the contribution of the ISAba1bla OXA-51 -like structure on carbapenem resistance varied, depending on its plasmid or chromosome location (18).…”

Section: Discussionmentioning

confidence: 99%

Multicenter Study of the Relationship between Carbapenem MIC Values and Clinical Outcome of Patients with Acinetobacter Bacteremia

Yang

Wang²,

Kuo

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) offer different recommendations for carbapenem MIC susceptibility breakpoints for species. In addition, the clinical efficacy of the intermediate category remains uncertain. This study was designed to determine the optimal predictive breakpoints based on the survival of patients with bacteremia treated with a carbapenem. We analyzed the 30-day mortality rates of 224 adults who received initial carbapenem monotherapy for the treatment of bacteremia at 4 medical centers over a 5-year period, according to the carbapenem MICs of the initial isolates. The 30-day mortality was about 2-fold greater in patients whose isolates had carbapenem MICs of ≥8 mg/liter than in those with isolates with MICs of ≤4 mg/liter. The differences were significant by bivariate analysis (53.1% [60/113] versus 25.2% [28/111], respectively; < 0.001) and on survival analysis by the log rank test ( < 0.001). Classification and regression tree analysis revealed a split between MICs of 4 and 8 mg/liter and predicted the same difference in mortality, with a value of<0.001. Carbapenem treatment for bacteremia caused by isolates with carbapenem MICs of ≥8 mg/liter was an independent predictor of 30-day mortality (odds ratio, 4.218; 95% confidence interval, 2.213 to 8.039; < 0.001). This study revealed that patients with bacteremia treated with a carbapenem had a more favorable outcome when the carbapenem MICs of their isolates were ≤4 mg/liter than those with MICs of ≥8 mg/liter.

show abstract

Clinical Variants of the Native Class D β-Lactamase of Acinetobacter baumannii Pose an Emerging Threat through Increased Hydrolytic Activity against Carbapenems

Cited by 19 publications

References 60 publications

Multiple substitutions lead to increased loop flexibility and expanded specificity in Acinetobacter baumannii carbapenemase OXA-239

Multiple substitutions lead to increased loop flexibility and expanded specificity in Acinetobacter baumannii carbapenemase OXA-239

The structure of a doripenem‐bound OXA‐51 class D β‐lactamase variant with enhanced carbapenemase activity

Multicenter Study of the Relationship between Carbapenem MIC Values and Clinical Outcome of Patients with Acinetobacter Bacteremia

Contact Info

Product

Resources

About