研究领域
Bioinorganic chemistry
Our research involves the study of two medically-important enzymes, metallo-b-lactamases (MBLs) and matrix metalloproteinases (MMPs). My lab utilizes pre-steady state kinetic studies to probe the kinetic mechanisms of these enzymes and spectroscopic and crystallographic studies to probe the structures of these enzymes. We utilize rapid freeze quench methods to trap reaction intermediates and EPR/EXAFS spectroscopies to characterize these intermediates.
MBLs - We are currently working on several MBLs in an effort to design clinical inhibitors of these enzymes, which confer antibiotic resistance to bacteria. With Larry Sutton at Sopharmia, Inc., we have been examining the inhibition properties of cephalosporins with styrylbenzene substituents as mechanism-based inhibitors.
With Walt Fast (UT-Austin), Seth Cohen (UCSD), and Robert Bonomo (Case Western), the Crowder, Tierney, and Page labs have started a NIH-funded project on which we are examining libraries of zinc binding groups, which will serve as the scaffold for new MBL inhibitors. With Brian Bennett (Marquette), the Crowder and Tierney labs are conducting EPR, NMR, UV-Vis, EXAFS, and DEER studies on several MBLs in an effort to understand the structures of the enyzmes during catalysis.
MMPs - We are currently working on several MMPs in an effort to understand how current inhibitors bind to these enzymes. We will examine several alternative zinc binding groups to determine whether the metal binding scaffold can afford binding specificity or selectivity.
近期论文
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H. Yang, K. Makaroff, N. Paz, M. Aitha, M.W. Crowder, and D.L. Tierney, "Metal-containing variants of MMP-1" Biochemistry (2015) submitted for publication.
T. Richmond, J. Buell, S. Pfeil, and M.W. Crowder, "Evidence-based recommendations for maximizing competitive swimming performance" J. Swimming Res. (2015) accepted for publication.
P. Oelschlaeger, M. Aitha, H. Yang, J. Kang, A. Zhang, E. Liu, J. Buynak, and M. Crowder, "Meropenem and chromacef intermediates observed in IMP-25 metallo-b-lactamase-catalyzed hydrolysis" Antimicro. Agents Chemo. (2015) accepted for publication.
M. Aitha, L. Moritz, I.D. Sahu, O. Sanyurah, Z. Roche, R. McCarrick, G.A. Lorigan, B. Bennett, and M.W. Crowder, "Conformational dynamics of metallo-β-lactamase CcrA during catalysis investigated by using DEER spectroscopy" J. Biol. Inorg. Chem. (2015) 20 (3) 585-594.
M. Aitha, A. Marts, A. Bergstrom, A. Moller, L. Moritz, L. Turner, J. Nix, R. Bonomo, R. Page, D.L. Tierney, M.W. Crowder, "Biochemical, mechanistic, and spectroscopic characterization of metallo-β-lactamase VIM-2" Biochemistry (2014) 53 (46) 7321-7331.
H. Yang, H. Young, L. Sutton, and M.W. Crowder, "Targeting metallo-carbapenemases via modulation of electronic properties of cephalosporins" Biochem. J. (2014) 464 (2) 271-279.
Y.L. Zhang, K.W. Yang, Y.J. Zhou, A.E. LaCuran, P. Oelschlaeger, and M.W. Crowder, "Diaryl-substituted azolthioacetamides: inhibitor discovery of New Delhi metallo-β-lactamase-1 (NDM-1)" ChemMedChem (2014) 9 (11) 2445-2448.
H. Yang, M. Aitha, A.R. Marts, A. Hetrick, B. Bennett, M.W. Crowder, and D.L. Tierney, "Spectroscopic and mechanistic studies of heterodimetallic forms of metallo-β-lactamase NDM-1" J. Am. Chem. Soc. (2014) 136 (20) 7273-7285.
M. Aitha, T.K. Richmond, Z. Hu, A. Hetrick, R. Reese, A. Gunther, R. McCarrick, B. Bennett, and M.W. Crowder, "Dilution of dipolar interactions in a spin-labeled, multimeric metalloenzyme for DEER studies" J. Inorg. Biochem. (2014) 136 40-46.
K.W. Yang, L. Fang, S.K. Yang, M. Aitha, A.E. LaCuran, P. Oelschlaeger, M.W. Crowder, “New β-phospholactam as a carbapenem transition state analog: synthesis of a broad-spectrum inhibitor of metallo-β-lactamases” Bioorg. Med. Chem. Lett. (2013) 23 (21) 5855-5859.
H. Heidari Torkabadi, T. Che, J. Shou, S. Shanmugam, M. Crowder, R. Bonomo, M. Pusztai-Carey, P. Carey, “Raman spectra of interchanging β-lactamase inhibitor intermediates on the millisecond time scale” J. Am. Chem. Soc. (2013) 135 (8) 2895-2898.
Y.L. Zhang, J.M. Xiao, J.L. Feng, K.W. Yang, L. Feng, L.S. Zhou, M.W. Crowder, “A novel fluorogenic substrate for dinuclear Zn(II)-containing metallo-β-lactamases ” Bioorg. Med. Chem. Lett. (2013) 23 (6) 1676-1679.
L.S. Zhou, K.W. Yang, L. Feng, J.M. Xiao, C.C. Liu, Y.L. Zhang, M.W. Crowder, “Novel fluorescent risedronates: synthesis, photodynamic inactivation, and imaging of Bacillus subtilis” Bioorg. Med. Chem. Lett. (2013) 23 (4) 949-954.
L. Feng, K.W. Yang, L.S. Zhou, J.M. Xiao, X. Yang, L. Zhai, Y.L. Zhang, and M.W. Crowder, “N-heterocyclic dicarboxylic acids: broad-spectrum inhibitors of metallo-β-lactamases with co-antibacterial effect against antibiotic resistant bacteria” (2012) Bioorg. Med. Chem. Lett. 22 (16) 5185-5189.
H. Yang, M. Aitha, A. Hetrick, T.K. Richmond, D.L. Tierney, and M.W. Crowder, “Mechanistic and spectroscopic studies on metallo-β-lactamase NDM-1” Biochemistry (2012) 51 3839-3847.
M.P. Hensley, T.S. Gunasekera, J.A. Easton, T.K. Sigdel, S.A. Sugarbaker, L. Klingbeil, R.M. Breece, D.L. Tierney, and M.W. Crowder, “Characterization of Zn(II)-responsive proteins YkgM and L31 in E. coli” J. Inorg. Biochem. (2012) 111 164-172.
C. Luxford, M.W. Crowder, and S.L. Bretz, “A symmetry POGIL activity for inorganic chemistry” J. Chem. Ed. (2012) 89(2) 211-214.
D. Griffin, T.K. Richmond, C.Sanchez-Geraci, A. Moller, R.M. Breece, D.L. Tierney, B. Bennett, and M.W. Crowder, “Structural and kinetic studies on metallo-β-lactamase IMP-1” Biochemistry (2011) 50 9125-9134.
M.P. Hensley, D.L. Tierney, and M.W. Crowder, “Zn(II) binding to E. coli 70S ribosomes” (2011) Biochemistry 50 9937-39.
K. Linenberger, S.L. Bretz, M.W. Crowder, R. McCarrick, D.L. Tierney, and G.A. Lorigan, “What is fresh meat’s true color? Investigating the effects of ligand binding on myoglobin using optical, electron paramagnetic resonance, and nuclear magnetic resonance spectroscopy” J. Chem. Ed. (2011) 88 223-225.
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