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姓名：杨科武 性别：男
部门：有机化学与化学生物学学部
职称：教授
邮箱：kwyang@nwu.edu.cn 电话： Phone/Fax: +86/0-29-8153-5035(O)
研究方向： Chemical Biology, Antibiotic Resistance, Metalloenzyme, Biopharmaceuticals
简 介
BIOGRAPHY
Professor Kewu Yang received his PhD in chemistry in 1994 from Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences. He joined the faculty at Fudan University as an associate professor in 1996, then pursued project antibiotic resistance in bacteria from National Institutes of Health (NIH) at Miami University since 1998, and followed serviced Girindus America Inc at the Medicinal Chemistry Department as a senior scientist to mastermind the research and development projects from Procter and Gamble and Aventis Pharmaceuticals. Dr. Yang joined the faculty at Northwest University as a Professor and a leading investigator in chemical biology in 2007, also a Chair Professor at Gothenburg University, Sweden, in 2016. He is amember of SIGMA XI, The Scientific Research Society.
RESEARCH INTERESTS
Yang group (Chemical Biology Lab, CBL) focus on important biomedical targets. We are using the tools of protein chemistry, organic synthesis, molecular biology and biophysics to develop clinically-useful compounds for the diagnoses and treatment of the biomedical targets including antibiotic resistant bacteria. We are particularly interested in taking amultidisciplinary approach to develop a Protein Chip technology for high throughput screening of the antibiotic resistant bacteria. Researchers in the group work at the interface of chemistry, biology, medicine and pharmaceuticals. We are currently engaging the following projects.
1. Metallo-β-lactamases (MβLs)
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The most common prescribed antibiotics are β-lactam compounds such as penicillins, cephalosporins and carbapenems. The overuse of antibiotics in the clinical setting has resulted in a large number of bacteria which are resistant to almost all antibiotics. The most common way for bacteria to become resistant to β-lactam antibiotics is to produce the metallo-β-lactamases (MβLs), which hydrolyze almost all β-lactam antibiotics. We are currently conducting inhibitor synthesis, spectroscopic and mechanistic characterization of interaction between inhibitors and MβLs by NMR, EPR, EXAFS and RFQ in an attempt to develop broad-spectrum inhibitors of the MβLs for combating antibiotic resistance.
2. D-ala-D-ala-Dipeptidase VanX
yangkw
Vancomycin inhibits bacterial cell wall synthesis by binding to the D-ala-D-alanine end of the pentapeptide via five hydrogen bonds, thereby preventing cross-linking of the pentapeptides to form the normal bacterial peptidoglycan layer. VanX hydrolyzes almost all of D-ala-D-alanyl dipeptides of the pentapeptides so that vancomycin loses the targets. Clearly, to produce tight-binding inhibitor of VanX is an effective way to combat vancomycin resistance in bacteria. Towards this goal, we are implementing rational strategy to design, synthesize and evaluate inhibitors of the VanX, to investigate structure-activity relationship (SAR), which is used for guiding design of new drugs.
3. Glyoxalase-II Isozymes
yangkw
Biochemical studies on glyoxalase system have implicated Glyoxalase-II (GLX-II) is in detoxification of cytotoxic 2-oxoaldehydes from the cell and the inhibitors of GLX-II can stop growth of tumors, because the tumors have no way to remove the toxic byproducts. In an effort to probe inhibition of GLX-II, we design, synthesize and evaluate glutathione derivatives as inhibitors, and investigated which substitutes on the inhibitor are essential for tight binding, and whether hydrophobic interactions contribute to the tight binding of the inhibitors. This study is targeted for development of potential antitumor reagents.
MAIN PROJECTS ACCOMPLISHED
> Antibiotic resistance (81361138018, 64020138804), NSFC-Swedish Research Council joint program, PI
> Activity monitoring and inhibition of metallo-β-lactamase in living bacterial cells (21572179), NSFC, PI
> Broad-spectrum inhibition of the specific compounds against super bugs (21272186), NSFC, PI
> Vancomycin resistance: structure optimization and activity of VanX inhibitors (20972127), NSFC, PI
> Foreign expert fund of National Personnel Ministry (20106100080), PI
> Doctoral fund of the Ministry of Education (200806970005), PI
> Overseas fund of National Personnel Ministry (SLZ2008013), PI
> Key fund for international cooperation of Shaanxi province (2014KW23-03), PI
> Key fund for international cooperation of Shaanxi province (2010KW-16), PI
> Natural science fund of Shaanxi province (2009JM2002), PI
> Research fund of Shaanxi Department of Education (09JK786), PI
> Development of prodrugs for the treatment of osteoporosis, Procter & Gamble, PI
> Synthetic development of anti-herpes compounds, Aventis Pharmaceuticals, PI
> Characterization of metallo-β-lactamases, National Institutes of Health (NIH), co-PI
> Characterization of metallo-β-lactamases from X. maltophilia, National Institutes of Health (NIH), co-PI
> Inhibition Studies on d-ala-d-ala dipeptidase VanX, National Science Fundation (NSF), co-PI
> Studies on glyoxalase II in arabidopsis thaliana, National Science Fundation (NSF), co-PI
INTERNATIONAL COLLABORATION
> Characterization of metallo-β-lactamases: Prof Michael Crowder, Miami University, USA
> Antibiotic resistance in bacteria: Prof Mate Erdelyi, University of Gothenburg, Sweden
> Docking study: Prof Peter Oelschlaeger, Western University of Health Sciences, USA
> EPR characterization: Prof Brian Bennett, The National Biomedical EPR Center, USA
> Crystal structure of metallo-β-lactamase: Prof James Spencer, University of Bristol, UK
> Structure of MβL-inhibitor complexs: Dr. Hanna-Kirsti Leiros, Arctic University of Norway
SELECTED PUBLICATIONS
KW Yang*, YJ Zhou, Y Ge, and YJ Zhang,“Real-time activity monitoring of New Delhi metallo-β-lactamase-1 in living bacterial cells by UV-Vis spectroscopy”, Chem. Commun., 2017, 53(57), 8014-8017.
XY Ouyang*, YN Chang, KW Yang*, WM Wang, JJ Bai, JW Wang, YJ Zhang, SY Wang, BB Xie, and LL Wang, “A DNA nanoribbon as a potent inhibitor of metallo-β-lactamases”, Chem. Commun., 2017, 53(63), 8878-8881.
YN Chang, Y Xiang, YJ Zhang, WM Wang, C Chen, P Oelschlaeger, KW Yang*, “Carbamylmethyl mercaptoacetate thioether: a novel scaffold for the development of L1 metallo-β-lactamase inhibitors”, ACS Med. Chem. Lett. 2017, 8, 527-532.
WJ Wang, Q Wang, Y Zhang, R Lu, YL Zhang, KW Yang*, JE Lei, Y He*, “Characterization of β-lactamase activity using isothermal titration calorimetry”, BBA-General Gubjects, 2017, 1861(8), 2031-2038.
L Zhai, and KW Yang*, “Porphyrin-vancomycin: a highly promising conjugate for the identification and photodynamic inactivation of antibiotic resistant Gram-positive pathogens”, Dyes and Pigments, 2015, 120, 228-238.
JM Xiao, L Feng, LS Zhou, HZ Gao, YL Zhang, KW Yang*, “Novel fluorescent cephalosporins: synthesis, antimicrobial activity and photodynamic inactivation of antibiotic resistant bacteria”, Eur. J. Med. Chem. 2013, 59, 150-159.
HZ Gao, KW Yang*, XL Wu, JY Liu, L Feng, JM Xiao, LS Zhou, C Jia, Z Shi, “Novel conjugation of norvancomycin-fluorescein for photodynamic inactivation of Bacillus subtilis”, ACS Bioconjugate Chem. 2011, 22, 2217−2221.
L Zhai, YL Zhang, JS Kang, P Oelschlaeger, L Xiao, SS Nie, and KW Yang*, "Triazolylthioacetamide: a valid scaffold for the development of New Delhi metallo-β-lactmase-1 (NDM-1) inhibitors", ACS Med. Chem. Lett. 2016, 7(4), 413-417.
T Christopeit, KW Yang, SK Yang, HK S. Leirosa, “The structure of the metallo-β-lactamase VIM-2 in complex with a triazolylthioacetamide inhibitor”, Acta Cryst. F. 2016, 72, 813-819.
XL Liu, KW Yang*, YJ Zhang, Y Ge, Y Xiang, YN Chang, P Oelschlaege, "Optimization of amino acid thioesters as inhibitors of metallo-β-lactamase L1", Bioorg. Med. Chem. Lett. 2016, 26(19), 4698-4671.
YL Zhang, YJ Zhang, WM Wang, KW Yang*, "Synthesis and inhibitory activity of acetamidephosphonic acids against metallo-β-lactamases", Phosphorus, Sulfur, and Silicon and the Related Elements, 2017, 192(1), 14-18.
LL Zhou, YQ Zhou, YL Tang, KW Yang, L Zhang, LX Gao, GF Zhang, ZW Gao, WQ Zhang, “Antibacterial Fischer Carbenoid CO-Releasing Molecules (Fc-CORMs)”, Chin. J. Org. Chem. 2016, 36, 2695-2703.
XL Liu, Y Shi, JS Kang, P Oelschlaeger, KW Yang*, “Amino acid thioester derivatives: a highly promising scaffold for the development of metallo-β-lactamase L1 inhibitors”, ACS Med. Chem. Lett. 2015, 6(6), 660–664.
SK Yang, JS Kang, P Oelschlaeger, KW Yang*, “Azolylthioacetamide: a highly promising scaffold for the development of metallo-β-lactamase inhibitors”, ACS Med. Chem. Lett. 2015, 6(4), 455-460.
YL Zhang, KW Yang*, YJ Zhou, AE LaCuran, P Oelschlaeger, MW Crowder, “Diaryl-substituted azolylthioacetamides: inhibitor discovery of New Delhi metallo-β-lactamase-1 (NDM-1)”, Chem Med Chem. 2014, 9(11), 2445-2448.
CC Liu, LS Zhou, JY Liu, JM Xiao, HZ Gao, KW Yang*, “Photoinactivation of vancomycin-resistant Enterococci and Bacillus subtilis by novel conjugate norvancomycin-rhodamine B”, New J. Chem. 2013, 37, 575-580.
L Feng, KW Yang*, SK Yang, M Aitha, AE LaCuran, P Oelschlaeger, MW Crowder*, “New β-phospholactam as acarbapenem transition state analog: synthesis of broad-spectrum inhibitor of metallo-β-lactamases”, Bioorg. Med. Chem. Lett. 2013, 23, 5855–5859.
LS Zhou, KW Yang*, L Feng, JM Xiao, CC Liu, YL Zhang, MW Crowder*, “Novel fluorescent risedronates: synthesis, photodynamic inactivation and imaging of Bacillus subtilis”, Bioorg. Med. Chem. Lett. 2013, 23, 949-954.
YL Zhang, JM Xiao, JL Feng, KW Yang*, L Feng, LS Zhou, MW Crowder*, “A novel fluorogenic substrate for dinuclear Zn(II)-containing metallo-β-lactamases”, Bioorg. Med. Chem. Lett. 2013, 23, 1676-1679.
X Yang, YJ Zhou, P He, YH Guo, CJ Liu, and KW Yang*, “Activation free energy of Zn(II), Co(II) binding to metallo-β-lactamase ImiS”, Chi. Chem. Lett. 2014, 25, 1323–1326.
Y Shi, L Feng, Q Yang, YJ Zhou, KW Yang*, “Thermokinetic evaluation of pyrrolidinedicarboxylic acid inhibiting cefalexin hydrolysis with metallo-β-lactamase L1 from Stenotrophomonas maltophilia”, Thermochimica Acta, 2013, 563, 46-50.
L Zhai, LS Zhou, CC Liu, Y Shi, YJ Zhou, KW Yang*, “Determination of thermodynamic parameters of benzylpenicillin hydrolysis by metallo-β-lactamase CcrA from Bacteroides fragilis”, Thermochimica Acta, 2013, 556, 54-57.
CC Liu, XB Zhao, KW Yang*, KZ Xu, L Zhai, X Yang, HZ Gao, “Exploring antibiotic resistance based on enzyme hydrolysis by microcalorimetry IV: determination of thermokinetic parameters of d-ala-d-ala hydrolysis with dipeptidase VanX”, J. Therm. Anal. Calorim. 2013, 111(3), 1663-1667.
L Zhai, KW Yang*, CC Liu, KZ Xu, X Yang, HZ Gao, Y Shi, L Feng, C Jia, LS Zhou, JM Xiao, “Exploring antibiotic resistance based on enzyme hydrolsis by microcalorimetryⅢ: determination of thermokinetic parameters of cefazolin hydrolysis with metallo-β-lactamase CcrA”, J. Therm. Anal. Calorim. 2013, 111(3), 1657-1661.
CC Liu, L Zhai, Y Shi, KW Yang*, “Purification of metallo-β-lactamase CcrA from Bacteroides fragilis with salting-out method”, Braz. Arch. Biol. Technol. 2013, 56(5), 811-816.
L Feng, KW Yang*, LS Zhou, JM Xiao, X Yang, L Zhai, YL Zhang, MW Crowder*, “N-heterocyclic dicarboxylic acids: broad-spectrum inhibitors of metallo-β-lactamases with co-antibacterial effect against antibiotic-resistant bacteria”, Bioorg. Med. Chem. Lett. 2012, 22, 5185–5189.
C Jia, KW Yang*, CC Liu, L Feng, JM Xiao, LS Zhou, YL Zhang, “Synthesis,characterization and activity of new phosphonate dipeptides as potential inhibitors of VanX”, Bioorg. Med. Chem. Lett. 2012, 22, 482-484.
L Zhai, KW Yang*, CC Liu, HZ Gao, X Yang, Y Shi, J Wen, “Thermokinetic characterization of imipenem hydrolysis with metallo-β-lactamase CcrA from Bacteroides fragilis”, Thermochimica Acta. 2012, 539, 67-70.
X Yang, L Feng, KZ Xu, HZ Gao, C Jia, CC Liu, JM Xiao, L Zhai, LS Zhou, KW Yang*, “Exploring antibiotic resistant mechanism by microcalorimetry II:determination of thermokinetic parameters of imipenem hydrolysis with metallo-β-lactamase ImiS”, J. Therm. Anal. Calorim. 2012, 110, 945-948.
HZ Gao, Q Yang, XY Yan, ZJ Wang, JL Feng, X Yang, SL Gao, L Feng, X Cheng, C Jia, KW Yang*, “Determination of thermodynamic carameters of penicillin Ghydrolysis catalyzed by metallo-β-lactamase L1 from Stenotrophomonas maltophilia”, J. Therm. Anal. Calorim. 2012, 107, 321-324.
KW Yang*, X Cheng, C Zhao, CC Liu, C Jia, L Feng, JM Xiao, LS Zhou, HZ Gao, X Yang, L Zhai, “Synthesis and activity study of phosphonamidate dipeptides as potential inhibitors of VanX”, Bioorg. Med. Chem. Lett. 2011, 21, 7224-7227.
HZ Gao and KW Yang*, “Antibiotic resistance in superbugs: research progress of the metallo-β-lactamases”, Chin. Pharm. J. 2011, 47(5), 325-330.
XB Zhao, ZH Zhang, XX Yan and KW Yang*, “Research process and application of bisphosphonate drugs”, Chin. J. Osteoporos, 2011, 17(10), 65-69.
Yan XY, Gao HZ, Feng JL, Yang X, Feng L, Cheng X, Jia C, Yang KW*, "Wild-type and Co(II)substituted metallo-β-lactamase L1: spectroscopic characterization and kinetic studies of catalyzing antibiotic hydrolysis", Chin. J. Antibiot. 2011, 36(5), 388-393.
Feng JL, Yang X, Yan XY, Gao HZ, Feng L, Cheng X, Jia C, Wu D, Yang KW*, "Expression,purification of ImiS and kinetic studies on hydrolysis of three type of β-lactam antibiotics catalyzed by ImiS", Chin. J. Antibiot. 2011, 36(3), 197-200.
A.L. Costello, G. Periyannan, K.W. Yang, M.W. Crowder*, D.L. Tierney, “Site selective binding of Zn(II)to metallo-β-lactamase L1 from Stenotrophomonas maltophilia”, J. Biol. Inorg. Chem. 2006, 11(3), 351-358.
A.L. Costello, N.P. Sharma, K.W. Yang, M.W. Crowder*, D.L. Tierney, “X-ray absorption spectroscopy of the zinc-binding sites in the class B2 metallo-β-lactamase ImiS from Aeromonas veronii bv. sobria”, Biochemistry, 2006, 45, 13650-13658.
G.R. Periyannan, A.L. Costello, D.L. Tierney, K.W. Yang, B. Bennett, M.W. Crowder*, “Sequential binding of cobalt(II)to metallo-β-lactamase CcrA”, Biochemistry, 2006, 45, 1313-1320.
N.P. Sharma, C. Hajdin, S. Chandrasekar, B. Bennett, K.W. Yang, M.W. Crowder*, “Mechanistic studies on the mononuclear Zn(II)-containing metallo-β-lactamase ImiS from Aeromonas sobria”, Biochemistry, 2006, 45, 10729-10738.
P.A. Crawford, K.W. Yang, N. Sharma, B. Bennett, M.W. Crowder*, "Spectroscopic studies on Co(II)-substituted metallo-β-lactamase ImiS from Aeromonas veronii bv.sobria", Biochemistry, 2005, 44, 5168-5176.
K.W. Yang, F.C. Golich, T.K. Sigdel, M.W.Crowder*, “Phosphinate,sulfonate and sulfonamidate dipeptides as potential inhibitors of aminopeptidase N”, Bioorg. Med. Chem. Lett. 2005, 15, 5150-5153.
G.P. Marasinghe, I.M. Sander, B. Bennett, G. Periyannan, K.W. Yang, C.A. Makaroff, M.W. Crowder*, “Structural studies on amitochondrial glyoxalase II”, J. Biol. Chem. 2005, 280, 40668-40675.
K.W. Yang and M.W. Crowder*, "A method for removing ethylenediaminetetraacetic acid from apo-proteins", Anal. Biochem. 2004, 329, 342-344.
K.W. Yang, D.N. Sobieski, A.L. Carenbauer, P.A. Crawford, C.A. Makaroff, M.W. Crowder*, “Explaining the inhibition of glyoxalase II by 9-fluorenylmethoxycarbonyl-protected glutathione derivatives”, Arch. Biochem. Biophys. 2003, 414, 271-278.
M.W. Crowder*, K.W. Yang, A.L. Carenbauer, G. Periyannan, M.E. Seifert, N.E. Rude, T.R. Walsh, “The problem of asolvent exposable disulfide when preparing Co(II)-substituted metallo-β-lactamase L1 from Stenotrophomonas maltophilia”, J. Biol. Inorg. Chem. 2001, 6, 91-99.
K.W. Yang, J.J. Brandt, L.L. Chatwood, M.W. Crowder*, “Phosphonamidate and phosphothioate dipeptides as potential inhibitors of VanX”, Bioorg. Med. Chem. Lett. 2000, 10, 1085-1087.
K.W. Yang, M.W. Crowder*, “Inhibition studies on the metallo-β-lactamase L1 rom Stenotrophomonas maltophilia”, Arch. Biochem. Biophys. 1999, 368, 1-6.
J.J. Brandt, L.L. Chatwood, K.W. Yang, M.W. Crowder*, “Continuous assay for VanX,the D-ala-D-ala dipeptidase required for high-level vancomycin resistance”, Anal. Biochem. 1999, 272, 94-99.
M.W. Crowder*, S. McMannus-Munoz, A.L. Carenbauer, M.Seifert, K.W. Yang, “Structure/function studies on metal-β-lactamase L1 from S.maltophilia”, J. Inorg. Biochem. 1999, 74, 106.
K.W. Yang, Y.Z. Wang, Z.X. Huang*, J.Sun, “Active site model of carbonic anhydrase:synthesis and crystal structure of functional tetrahedral zinc complex with hydrotris(3-phenyl-5-methylpyrazol-1-yl)borate”, Polyhedron, 1997, 16, 109-112.
K.W. Yang, Y.Z. Wang, Z.X. Huang*, J.Sun, “Synthesis,characterization and x-ray crystal structure of Zn(II)complex with poly-nitrogen ligand[(3-HB(3,5-Me2pz)3]2Zn2C6H5CH3”, Polyhedron, 1997, 16, 1297-1300.
Yang K.W., Yin Y.Q., Wang Y.Z., Huang Z.X.*, “Studies on synthesis,characterization and quantum chemistry of carbonic anhydrase active site model compounds[(3-HB(3-Phpz)3ZnX](X=Cl,Br,Iand NO3)”, Acta Chimia Sinica, 1997, 55, 209-214.
K.W. Yang, Y.Q. Yin, Z.X. Huang*, Y.H. Wang, “Synthesis and crystal structure of zinc complex[Zn(P(py)3)2][Zn(NCS)4(MeCN)]”, Polyhedron, 1996, 15, 79-81.
K.W. Yang, Y.Q. Yin*, D.S. Jin, “An active site model for carbonic anhydrase-synthesis and crystal structure of[(3-HB(3-Phpz)3]ZnBr”, Polyhedron, 1995, 14, 1021-1023.
K.W. Yang, Y.Q. Yin*, D.S. Jin, “Preparation of copper(I)complexes with novel pyrazolyl borates”, Chi. Chem. Lett. 1994, 5, 341-342.
Yang K.W., Wu J.G., Wang L.F.*, Yang Z.Y., “Determination of stability constants of rare earth(III)complexes by hypersensitive transition method”,J. Lanzhou Uni.(Nat.Sci), 1994, 30, 49-52.
Yang Z.Y., Wang L.F.*, Wu J.G., Yang K.W., Zhu Y., “Studies on synthesis,characterization and electrical conductivity of complexes of 3d transition metal with 2-oxo-propionic acid(4-pyridinecarbonyl)hydrazone”, Acta Chimia Sinica, 1993, 51, 184-190.
Yang K.W., Wu J.G., Wang L.F.*, Dong F., “Determination of stability constants of Nd(III)complexes with pantothenate by absorption spectroscopy”, Chi. J. Inorg. Chem. 1993, 9, 271-274.
Wang L.F.*, Yang K.W., Wu J.G., “Determination of thermodynamical functions of neodymium pyridoxol complexes by hypersensitive transition method”, Chi. J. Appl. Chem. 1993, 10, 84-86.
Yang Z.Y., Ai J., Wang L.F.*, Wu J.G., Yang K.W., “Studies on the synthesis characterization and antitumor activity of the temary complexes of rare earth(III)with schiff base”, J. Lanzhou Uni.(Nat.Sci.), 1993, 29, 162-166.
Yang Z.Y., Wang L.F.*, Wu J.G., Li X.Y., Yang K.W., Wang Q., “Studies on anticancer activity of some rare earth(III)complexes with schif base”, Chi. Sci. Bull. 1992, 9, 813-816.
K.W. Yang, L.F. Wang*, J.G. Wu, F. Dong, “Synthesis,characterization and antioxidative activity of new vitamin B6 triethanolamine rare earth(III)complexes”, J. Inorg. Biochem. 1993, 52, 145-150.
K.W. Yang, L.F. Wang*, J.G. Wu, Z.Y. Yang, X. Gao, “Synthesis,characterization and antioxidative activity of vitamin B6 rare earth(III)complexes”, J. Inorg. Biochem. 1993, 52, 151-155.
**Mailing Address:
Dr. Kewu Yang, College of Chemistry and Materials Science, Northwest University, 1 University Ave. Xi'an 710127, PR China.
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发表于 2017-8-25 08:36:39
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