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

Abstract

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. We found that these results reveal worrying trends in themore » enhancement of substrate spectrum of class D β-lactamases, but may also provide a map for β-lactam improvement.« less

Authors:
 [1];  [1];  [1];  [1];  [2];  [3];  [1];  [3];  [4];  [2];  [1];  [1]
+ Show Author Affiliations
  1. Grand Valley State Univ., Allendale, MI (United States). Dept. of Chemistry
  2. Grand Valley State Univ., Allendale, MI (United States). Dept. of Cell and Molecular Biology
  3. Case Western Reserve Univ., Cleveland, OH (United States). Dept. of Medicine, Pharmacology, Biochemistry, and Molecular Biology and Microbiology
  4. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). UT/ORNL Center for Molecular Biophysics, Biosciences Division
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1178836
Grant/Contract Number:  
AC02-06CH11357; 1R15AI082416; R15AI094489; 1I01BX001974; R01AI100560; R01 AI063517; P41GM103712; 085P1000817
Resource Type:
Accepted Manuscript
Journal Name:
Biochemistry
Additional Journal Information:
Journal Volume: 54; Journal Issue: 10; Journal ID: ISSN 0006-2960
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Mitchell, Joshua M., Clasman, Jozlyn R., June, Cynthia M., Kaitany, Kip-Chumba J., LaFleur, James R., Taracila, Magdalena A., Klinger, Neil V., Bonomo, Robert A., Wymore, Troy, Szarecka, Agnieszka, Powers, Rachel A., and Leonard, David A. Structural Basis of Activity against Aztreonam and Extended Spectrum Cephalosporins for Two Carbapenem-Hydrolyzing Class D β-Lactamases from Acinetobacter baumannii. United States: N. p., 2015. Web. doi:10.1021/bi501547k.
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Mitchell, Joshua M., Clasman, Jozlyn R., June, Cynthia M., Kaitany, Kip-Chumba J., LaFleur, James R., Taracila, Magdalena A., Klinger, Neil V., Bonomo, Robert A., Wymore, Troy, Szarecka, Agnieszka, Powers, Rachel A., & Leonard, David A. Structural Basis of Activity against Aztreonam and Extended Spectrum Cephalosporins for Two Carbapenem-Hydrolyzing Class D β-Lactamases from Acinetobacter baumannii. United States. https://doi.org/10.1021/bi501547k
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Mitchell, Joshua M., Clasman, Jozlyn R., June, Cynthia M., Kaitany, Kip-Chumba J., LaFleur, James R., Taracila, Magdalena A., Klinger, Neil V., Bonomo, Robert A., Wymore, Troy, Szarecka, Agnieszka, Powers, Rachel A., and Leonard, David A. Tue . "Structural Basis of Activity against Aztreonam and Extended Spectrum Cephalosporins for Two Carbapenem-Hydrolyzing Class D β-Lactamases from Acinetobacter baumannii". United States. https://doi.org/10.1021/bi501547k. https://www.osti.gov/servlets/purl/1178836.
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@article{osti_1178836,
title = {Structural Basis of Activity against Aztreonam and Extended Spectrum Cephalosporins for Two Carbapenem-Hydrolyzing Class D β-Lactamases from Acinetobacter baumannii},
author = {Mitchell, Joshua M. and Clasman, Jozlyn R. and June, Cynthia M. and Kaitany, Kip-Chumba J. and LaFleur, James R. and Taracila, Magdalena A. and Klinger, Neil V. and Bonomo, Robert A. and Wymore, Troy and Szarecka, Agnieszka and Powers, Rachel A. and Leonard, David A.},
abstractNote = {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. We found that 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.},
doi = {10.1021/bi501547k},
journal = {Biochemistry},
number = 10,
volume = 54,
place = {United States},
year = {Tue Feb 24 00:00:00 EST 2015},
month = {Tue Feb 24 00:00:00 EST 2015}
}
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https://doi.org/10.1021/bi501547k
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    Intrinsic Class D β-Lactamases of Clostridium difficile
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    • Moural, Timothy W.; White, Dawanna Shar-Day; Choy, Cindy J.
    • International Journal of Molecular Sciences, Vol. 20, Issue 13
    • DOI: 10.3390/ijms20133247

    Genetic and Biochemical Characterization of OXA-405, an OXA-48-Type Extended-Spectrum β-Lactamase without Significant Carbapenemase Activity
    journal, April 2015

    • Dortet, Laurent; Oueslati, Saoussen; Jeannot, Katy
    • Antimicrobial Agents and Chemotherapy, Vol. 59, Issue 7
    • DOI: 10.1128/aac.05058-14

    Antimicrobial Resistance Conferred by OXA-48 β-Lactamases: Towards a Detailed Mechanistic Understanding
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    • Hirvonen, Viivi H. A.; Spencer, James; van der Kamp, Marc W.
    • Antimicrobial Agents and Chemotherapy, Vol. 65, Issue 6
    • DOI: 10.1128/aac.00184-21

    Structural Analysis of The OXA-48 Carbapenemase Bound to A “Poor” Carbapenem Substrate, Doripenem
    journal, September 2019

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