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

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.

doi:10.1021/bi501547k

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

Journal Article · Tue Feb 24 00:00:00 EST 2015 · Biochemistry

DOI:https://doi.org/10.1021/bi501547k· OSTI ID:1178836

Mitchell, Joshua M. ^[1]; Clasman, Jozlyn R. ^[1]; June, Cynthia M. ^[1]; Kaitany, Kip-Chumba J. ^[1]; LaFleur, James R. ^[2]; Taracila, Magdalena A. ^[3]; Klinger, Neil V. ^[1]; Bonomo, Robert A. ^[3]; Wymore, Troy ^[4]; Szarecka, Agnieszka ^[2]; Powers, Rachel A. ^[1]; Leonard, David A. ^[1]

Grand Valley State Univ., Allendale, MI (United States). Dept. of Chemistry
Grand Valley State Univ., Allendale, MI (United States). Dept. of Cell and Molecular Biology
Case Western Reserve Univ., Cleveland, OH (United States). Dept. of Medicine, Pharmacology, Biochemistry, and Molecular Biology and Microbiology
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). UT/ORNL Center for Molecular Biophysics, Biosciences Division

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.

View Accepted Manuscript (DOE)

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1178836

Journal Information:: Biochemistry, Journal Name: Biochemistry Journal Issue: 10 Vol. 54; ISSN 0006-2960

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (53)

CHARMM: The biomolecular simulation program Brooks, B. R.; Brooks, C. L.; Mackerell, A. D. Journal of Computational Chemistry, Vol. 30, Issue 10 https://doi.org/10.1002/jcc.21287	journal	July 2009
A revised set of potentials for β-turn formation in proteins Hutchinson, E. Gail; Thornton, Janet M. Protein Science, Vol. 3, Issue 12 https://doi.org/10.1002/pro.5560031206	journal	December 1994
Ceftazidime-Avibactam: a Novel Cephalosporin/β-lactamase Inhibitor Combination Zhanel, George G.; Lawson, Christopher D.; Adam, Heather Drugs, Vol. 73, Issue 2 https://doi.org/10.1007/s40265-013-0013-7	journal	February 2013
Calculation of protein extinction coefficients from amino acid sequence data Gill, Stanley C.; von Hippel, Peter H. Analytical Biochemistry, Vol. 182, Issue 2 https://doi.org/10.1016/0003-2697(89)90602-7	journal	November 1989
Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction Yung-Chi, Cheng; Prusoff, William H. Biochemical Pharmacology, Vol. 22, Issue 23 https://doi.org/10.1016/0006-2952(73)90196-2	journal	December 1973
Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes Ryckaert, Jean-Paul; Ciccotti, Giovanni; Berendsen, Herman J. C. Journal of Computational Physics, Vol. 23, Issue 3 https://doi.org/10.1016/0021-9991(77)90098-5	journal	March 1977
VMD: Visual molecular dynamics Humphrey, William; Dalke, Andrew; Schulten, Klaus Journal of Molecular Graphics, Vol. 14, Issue 1 https://doi.org/10.1016/0263-7855(96)00018-5	journal	February 1996
Evolution of an Antibiotic Resistance Enzyme Constrained by Stability and Activity Trade-offs Wang, Xiaojun; Minasov, George; Shoichet, Brian K. Journal of Molecular Biology, Vol. 320, Issue 1 https://doi.org/10.1016/S0022-2836(02)00400-X	journal	June 2002
Evidence of dimerisation among class D β-lactamases: kinetics of OXA-14 β-lactamase Danel, Franck; Frère, Jean-Marie; Livermore, David M. Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, Vol. 1546, Issue 1 https://doi.org/10.1016/S0167-4838(01)00133-9	journal	March 2001
Mutagenesis of amino acid residues in the SHV-1 β-lactamase: the premier role of Gly238Ser in penicillin and cephalosporin resistance Hujer, Andrea M.; Hujer, Kristine M.; Bonomo, Robert A. Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, Vol. 1547, Issue 1 https://doi.org/10.1016/S0167-4838(01)00164-9	journal	May 2001
Crystal Structure of the OXA-48 β-Lactamase Reveals Mechanistic Diversity among Class D Carbapenemases Docquier, Jean-Denis; Calderone, Vito; De Luca, Filomena Chemistry & Biology, Vol. 16, Issue 5 https://doi.org/10.1016/j.chembiol.2009.04.010	journal	May 2009
Structural Basis for Carbapenemase Activity of the OXA-23 β-Lactamase from Acinetobacter baumannii Smith, Clyde A.; Antunes, Nuno Tiago; Stewart, Nichole K. Chemistry & Biology, Vol. 20, Issue 9 https://doi.org/10.1016/j.chembiol.2013.07.015	journal	September 2013
Structures of the Class D Carbapenemase OXA-24 from Acinetobacter baumannii in Complex with Doripenem Schneider, Kyle D.; Ortega, Caleb J.; Renck, Nicholas A. Journal of Molecular Biology, Vol. 406, Issue 4 https://doi.org/10.1016/j.jmb.2010.12.042	journal	March 2011
MMTSB Tool Set: enhanced sampling and multiscale modeling methods for applications in structural biology Feig, Michael; Karanicolas, John; Brooks, Charles L. Journal of Molecular Graphics and Modelling, Vol. 22, Issue 5 https://doi.org/10.1016/j.jmgm.2003.12.005	journal	May 2004
Class D β-Lactamases: A Reappraisal after Five Decades Leonard, David A.; Bonomo, Robert A.; Powers, Rachel A. Accounts of Chemical Research, Vol. 46, Issue 11 https://doi.org/10.1021/ar300327a	journal	July 2013
Structures of Ceftazidime and Its Transition-State Analogue in Complex with AmpC β-Lactamase: Implications for Resistance Mutations and Inhibitor Design ^† ^, ^‡ Powers, Rachel A.; Caselli, Emilia; Focia, Pamela J. Biochemistry, Vol. 40, Issue 31 https://doi.org/10.1021/bi0109358	journal	August 2001
Mutation of the Active Site Carboxy-Lysine (K70) of OXA-1 β-Lactamase Results in a Deacylation-Deficient Enzyme Schneider, Kyle D.; Bethel, Christopher R.; Distler, Anne M. Biochemistry, Vol. 48, Issue 26 https://doi.org/10.1021/bi900448u	journal	July 2009
Critical Role of Tryptophan 154 for the Activity and Stability of Class D β-Lactamases ^, Baurin, Stéphane; Vercheval, Lionel; Bouillenne, Fabrice Biochemistry, Vol. 48, Issue 47 https://doi.org/10.1021/bi901548c	journal	November 2009
Structure of the Extended-Spectrum Class C β-Lactamase of Enterobacter cloacae GC1, a Natural Mutant with a Tandem Tripeptide Insertion ^† ^, ^‡ Crichlow, Gregg V.; Kuzin, Alexandre P.; Nukaga, Michiyoshi Biochemistry, Vol. 38, Issue 32 https://doi.org/10.1021/bi9908787	journal	August 1999
X-ray Crystal Structure of the Acylated β-Lactam Sensor Domain of BlaR1 from Staphylococcus aureus and the Mechanism of Receptor Activation for Signal Transduction Birck, Catherine; Cha, Joo Young; Cross, Jason Journal of the American Chemical Society, Vol. 126, Issue 43 https://doi.org/10.1021/ja044742u	journal	November 2004
Refined crystal structure of β-lactamase from Citrobacter freundiiindicates a mechanism for β-lactam hydrolysis Oefner, C.; D'Arcy, A.; Daly, J. J. Nature, Vol. 343, Issue 6255 https://doi.org/10.1038/343284a0	journal	January 1990
The role of OXA-1 β-lactamase Asp66 in the stabilization of the active-site carbamate group and in substrate turnover Leonard, David A.; Hujer, Andrea M.; Smith, Brian A. Biochemical Journal, Vol. 410, Issue 3 https://doi.org/10.1042/BJ20070573	journal	February 2008
Three factors that modulate the activity of class D β-lactamases and interfere with the post-translational carboxylation of Lys70 Vercheval, Lionel; Bauvois, Cédric; di Paolo, Alexandre Biochemical Journal, Vol. 432, Issue 3 https://doi.org/10.1042/BJ20101122	journal	November 2010
Comparison of simple potential functions for simulating liquid water Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D. The Journal of Chemical Physics, Vol. 79, Issue 2 https://doi.org/10.1063/1.445869	journal	July 1983
Particle mesh Ewald: An N ⋅log( N ) method for Ewald sums in large systems Darden, Tom; York, Darrin; Pedersen, Lee The Journal of Chemical Physics, Vol. 98, Issue 12 https://doi.org/10.1063/1.464397	journal	June 1993
Crystal structure of the carbapenemase OXA-24 reveals insights into the mechanism of carbapenem hydrolysis Santillana, E.; Beceiro, A.; Bou, G. Proceedings of the National Academy of Sciences, Vol. 104, Issue 13 https://doi.org/10.1073/pnas.0607557104	journal	March 2007
Evolution to carbapenem-hydrolyzing activity in noncarbapenemase class D -lactamase OXA-10 by rational protein design De Luca, F.; Benvenuti, M.; Carboni, F. Proceedings of the National Academy of Sciences, Vol. 108, Issue 45 https://doi.org/10.1073/pnas.1110530108	journal	October 2011
Critical involvement of a carbamylated lysine in catalytic function of class D -lactamases Golemi, D.; Maveyraud, L.; Vakulenko, S. Proceedings of the National Academy of Sciences, Vol. 98, Issue 25 https://doi.org/10.1073/pnas.241442898	journal	November 2001
Acyl-intermediate Structures of the Extended-spectrum Class A β-Lactamase, Toho-1, in Complex with Cefotaxime, Cephalothin, and Benzylpenicillin Shimamura, Tatsuro; Ibuka, Akiko; Fushinobu, Shinya Journal of Biological Chemistry, Vol. 277, Issue 48 https://doi.org/10.1074/jbc.M207884200	journal	September 2002
Laboratory mutants of OXA-10 beta-lactamase giving ceftazidime resistance in Pseudomonas aeruginosa Danel, F. Journal of Antimicrobial Chemotherapy, Vol. 43, Issue 3 https://doi.org/10.1093/jac/43.3.339	journal	March 1999
Detection of a new extended-spectrum oxacillinase in Pseudomonas aeruginosa Fournier, D.; Hocquet, D.; Dehecq, B. Journal of Antimicrobial Chemotherapy, Vol. 65, Issue 2 https://doi.org/10.1093/jac/dkp438	journal	December 2009
Ceftazidime-hydrolysing -lactamase OXA-145 with impaired hydrolysis of penicillins in Pseudomonas aeruginosa Hocquet, D.; Colomb, M.; Dehecq, B. Journal of Antimicrobial Chemotherapy, Vol. 66, Issue 8 https://doi.org/10.1093/jac/dkr187	journal	June 2011
Activity of BAL30072 alone or combined with -lactamase inhibitors or with meropenem against carbapenem-resistant Enterobacteriaceae and non-fermenters Mushtaq, S.; Woodford, N.; Hope, R. Journal of Antimicrobial Chemotherapy, Vol. 68, Issue 7 https://doi.org/10.1093/jac/dkt050	journal	February 2013
A general method of in vitro preparation and specific mutagenesis of DNA fragments: study of protein and DNA interactions Higuchi, Russell; Krummel, Barbara; Saiki, Randall Nucleic Acids Research, Vol. 16, Issue 15 https://doi.org/10.1093/nar/16.15.7351	journal	January 1988
The Class D β-lactamase family: residues governing the maintenance and diversity of function Szarecka, Agnieszka; Lesnock, Kimberly R.; Ramirez-Mondragon, Carlos A. Protein Engineering, Design and Selection, Vol. 24, Issue 10 https://doi.org/10.1093/protein/gzr041	journal	August 2011
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
Data processing and analysis with the autoPROC toolbox Vonrhein, Clemens; Flensburg, Claus; Keller, Peter Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444911007773	journal	March 2011
The CCP4 suite programs for protein crystallography No authors listed Acta Crystallographica Section D Biological Crystallography, Vol. 50, Issue 5, p. 760-763 https://doi.org/10.1107/S0907444994003112	journal	September 1994
Refinement of Macromolecular Structures by the Maximum-Likelihood Method Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3 https://doi.org/10.1107/S0907444996012255	journal	May 1997
Comparison of -lactamases of classes A and D: 1.5-A crystallographic structure of the class D OXA-1 oxacillinase Sun, T. Protein Science, Vol. 12, Issue 1 https://doi.org/10.1110/ps.0224303	journal	January 2003
OXA-163, an OXA-48-Related Class D β-Lactamase with Extended Activity Toward Expanded-Spectrum Cephalosporins Poirel, Laurent; Castanheira, Mariana; Carrër, Amélie Antimicrobial Agents and Chemotherapy, Vol. 55, Issue 6 https://doi.org/10.1128/AAC.00022-11	journal	March 2011
Structures of the Class D Carbapenemases OXA-23 and OXA-146: Mechanistic Basis of Activity against Carbapenems, Extended-Spectrum Cephalosporins, and Aztreonam Kaitany, Kip-Chumba J.; Klinger, Neil V.; June, Cynthia M. Antimicrobial Agents and Chemotherapy, Vol. 57, Issue 10 https://doi.org/10.1128/AAC.00762-13	journal	July 2013
Emergence and Distribution of Plasmids Bearing the blaOXA-51-Like Gene with an Upstream ISAba1 in Carbapenem-Resistant Acinetobacter baumannii Isolates in Taiwan Chen, T. -L.; Lee, Y. -T.; Kuo, S. -C. Antimicrobial Agents and Chemotherapy, Vol. 54, Issue 11 https://doi.org/10.1128/AAC.00764-10	journal	August 2010
Identification of Diverse OXA-40 Group Carbapenemases, Including a Novel Variant, OXA-160, from Acinetobacter baumannii in Pennsylvania Tian, Guo-Bao; Adams-Haduch, Jennifer M.; Bogdanovich, Tatiana Antimicrobial Agents and Chemotherapy, Vol. 55, Issue 1 https://doi.org/10.1128/AAC.01155-10	journal	November 2010
Structural Origins of Oxacillinase Specificity in Class D β-Lactamases June, Cynthia M.; Vallier, Beth C.; Bonomo, Robert A. Antimicrobial Agents and Chemotherapy, Vol. 58, Issue 1 https://doi.org/10.1128/AAC.01483-13	journal	October 2013
Diversity, Epidemiology, and Genetics of Class D -Lactamases Poirel, L.; Naas, T.; Nordmann, P. Antimicrobial Agents and Chemotherapy, Vol. 54, Issue 1 https://doi.org/10.1128/AAC.01512-08	journal	August 2009
Crystal Structure of Carbapenemase OXA-58 from Acinetobacter baumannii Smith, Clyde A.; Antunes, Nuno Tiago; Toth, Marta Antimicrobial Agents and Chemotherapy, Vol. 58, Issue 4 https://doi.org/10.1128/AAC.01983-13	journal	January 2014
OXA-207, a Novel OXA-24 Variant with Reduced Catalytic Efficiency against Carbapenems in Acinetobacter pittii from Spain Cayô, Rodrigo; Merino, María; Ruiz del Castillo, Belén Antimicrobial Agents and Chemotherapy, Vol. 58, Issue 8 https://doi.org/10.1128/AAC.02633-13	journal	June 2014
A Case of IMP-4-, OXA-421-, OXA-96-, and CARB-2-Producing Acinetobacter pittii Sequence Type 119 in Australia Kamolvit, Witchuda; Derrington, Petra; Paterson, David L. Journal of Clinical Microbiology, Vol. 53, Issue 2 https://doi.org/10.1128/JCM.02726-14	journal	November 2014
The Rise of Carbapenem-Resistant Acinetobacter baumannii A. Evans, Benjamin; Hamouda, Ahmed; G. B. Amyes, Sebastian Current Pharmaceutical Design, Vol. 19, Issue 2 https://doi.org/10.2174/138161213804070285	journal	January 2013
β-Lactam Antibiotics Renaissance Qin, Wenling; Panunzio, Mauro; Biondi, Stefano Antibiotics, Vol. 3, Issue 2 https://doi.org/10.3390/antibiotics3020193	journal	May 2014

Cited By (6)

Antimicrobial Resistance Conferred by OXA-48 β-Lactamases: Towards a Detailed Mechanistic Understanding Hirvonen, Viivi H. A.; Spencer, James; van der Kamp, Marc W. Antimicrobial Agents and Chemotherapy, Vol. 65, Issue 6 https://doi.org/10.1128/aac.00184-21	journal	May 2021
A gratuitous β-Lactamase inducer uncovers hidden active site dynamics of the Staphylococcus aureus BlaR1 sensor domain Frederick, Thomas E.; Peng, Jeffrey W. PLOS ONE, Vol. 13, Issue 5 https://doi.org/10.1371/journal.pone.0197241	journal	May 2018
Structural Analysis of The OXA-48 Carbapenemase Bound to A “Poor” Carbapenem Substrate, Doripenem Papp-Wallace, Krisztina M.; Kumar, Vijay; Zeiser, Elise T. Antibiotics, Vol. 8, Issue 3 https://doi.org/10.3390/antibiotics8030145	journal	September 2019
Genetic and Biochemical Characterization of OXA-405, an OXA-48-Type Extended-Spectrum β-Lactamase without Significant Carbapenemase Activity Dortet, Laurent; Oueslati, Saoussen; Jeannot, Katy Antimicrobial Agents and Chemotherapy, Vol. 59, Issue 7 https://doi.org/10.1128/aac.05058-14	journal	April 2015
Intrinsic Class D β-Lactamases of Clostridium difficile Toth, Marta; Stewart, Nichole K.; Smith, Clyde mBio, Vol. 9, Issue 6 https://doi.org/10.1128/mbio.01803-18	journal	December 2018
Crystal Structure of Phosphoserine BlaC from Mycobacterium tuberculosis Inactivated by Bis(Benzoyl) Phosphate Moural, Timothy W.; White, Dawanna Shar-Day; Choy, Cindy J. International Journal of Molecular Sciences, Vol. 20, Issue 13 https://doi.org/10.3390/ijms20133247	journal	July 2019

Similar Records

The Drug-Resistant Variant P167S Expands the Substrate Profile of CTX-M β-Lactamases for Oxyimino-Cephalosporin Antibiotics by Enlarging the Active Site upon Acylation

Journal Article · Tue Jun 13 20:00:00 EDT 2017 · Biochemistry · OSTI ID:1418300

Sulfonamidoboronic Acids as “Cross-Class” Inhibitors of an Expanded-Spectrum Class C Cephalosporinase, ADC-33, and a Class D Carbapenemase, OXA-24/40: Strategic Compound Design to Combat Resistance in Acinetobacter baumannii

Journal Article · Thu Mar 23 20:00:00 EDT 2023 · Antibiotics · OSTI ID:2423670

C6 Hydroxymethyl-Substituted Carbapenem MA-1-206 Inhibits the Major Acinetobacter baumannii Carbapenemase OXA-23 by Impeding Deacylation

Journal Article · Wed Apr 13 20:00:00 EDT 2022 · mBio (Online) · OSTI ID:1903998

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES

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

Citation Formats

References (53)

Cited By (6)

Similar Records

Related Subjects