Molecular evolution and binding free energy analysis on substrates of KPC carbapenemases

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Author:
MI Zu-huang(Department of Bioinformatics,Wuxi Clone Gen-Tech Institute,Wuxi 214026,China)
WENG Xing-bei()
QIN Ling(Department of Bioinformatics,Wuxi Clone Gen-Tech Institute,Wuxi 214026,China)
Journal Title:
CHINESE JOURNAL OF CLINICAL INFECTIOUS DISEASES
Issue:
Volume 3, Issue 03, 2010
DOI:
10.3760/cma.j.issn.1674-2397.2010.03.002
Key Word:
Evolution,molecular;Carbapenemase;Molecular docking;β-lactam;Binding free energy

Abstract: Objective To analyze molecular evolution and binding free energies in substrates of KPC-2,KPC-5 and KPC-10 carbapenemases.Methods Minimum Evolution method in MEGA 4.1 was used to analyze molecular evolution of KPC-2,KPC-5 and KPC-10 carbapenemases,Dock module in ArgusLab 4.1 was used to perform molecular docking of these 3 carbapenemases to 10 kinds of β-lactams substrates,and calculate binding free energies(△G).Results Ambler Class A β-lactamases with carbapenemase activities were grouped in the same cluster and had good conservation,while ordinary Ambler Class A β-lactamases without carbapenemase activities were groupod in the other cluster.Binding free energies of KPC-2,KPC-5 and KPC-10 carbapenemases were lower to carbapenem antibiotics than the thirdgeneration cephalosporins,while binding free energies to aztreonam and clavulanic acid were of comparatively higher levels.Conclusion Catalytic activities of KPC to carbapenem antibiotics are higher than those to the third-generation cephalosporins,but the activities to aztreonam and clavulanic acid are low.

  • [1]Yigit H,Queenan AM,Anderson GJ,et al.Novel carbapenemhydrolyzing beta-lactamase,KPC-1,from a carbapenem-resistant strain of Klebsiella pneumoniae.Antimicrob Agents Chemother,2001,45(4):1151-1161.
  • [2]Zhang R,Zhou HW,Cai JC,et al.Plasmid-mediated carbapenem-hydrolysing beta-lactamase KPC-2 in carbapenemresistant Serratia marcescens isolates from Hangzhou,China.J Antimicrob Chemother,2007,59(3):574-576.
  • [3]Petrella S,Ziental-Gelus N,Mayer C,et al.Genetic and structural insightB into the dissemination potential of the extremely broad-spectrum class A beta-lactamase KPC-2 identified in an Escherichia coli strain and an Enterobacter cloacae strain isolated from the 8anle patient in France.Antimicrob Agents Chemother,2008,52(10):3725-3736.
  • [4]Wolter DJ,Kurpiel PM,Woodford N,et al.Phenotypic and enzymatic comparative analysis between the novel KPC variant,KPC-5,and its evolutionary variants,KPC-2 and KPC-4.Antimicrob Agents Chemother,2009,53(2):557-562.
  • [5]Akpaka PE,Swanston WH,Ihemere HN,et al.Emergence of KPC-producing Pseudomonas aeruginosa in Trinidad and Tobago.J Clin Microbial,2009,47(8):2670-2671.
  • [6]Bobledo IE,Aquino EE,SantéMI,et al.Detection of KPC in Acimatobacter spp.in Puerto Rico.Antimicrob Agents Chemother,2010,54(3):1354-1357.
  • [7]Ke W,Bethel CR,Thomson JM,et al.Crystal structure of KPC-2:insights into carbapenemase activity in Class A beta-lactamases.Biochemistry,2007,46(19):5732-5740.
  • [8]陈代杰.抗菌药物与细菌耐药性.上海:华东理工大学出版社,2001:84-85.
  • [9]Petrella S,Ziental-Gelus N,Mayer C,et al.Genetic and structural insighIs into the dissemination potential of the extremely broad-spectrum class A beta-laetamase KPC-2 identified in an Escherichia coli strain and an Enterobacter cloacae strain isolated from the same patient in France.Antimicrob Agents Chemother,2008,52(10):3725-3736.
  • [10]Santillana E,Beceiro A,Bou G,et al.Crystal structure of the carbapenemase OXA-24 reveals insights into the mechanism of carbapenem hydrolysis.Proc Natl Aead Sci U S A,2007,104(13):5354-5359.
  • [11]Teotico DG,Babaoglu K,Recklin GJ,et al.Docking for fragment inhibitors of AmpC beta-lactamase.Proc Natl Acad Sei U S A,2009,106(18):7455-7460.
  • [12]Horsfall LE,Garau G,Lienard BMR,et al.Competitive inhibitors of the CphA metallo-beta-lactamase from Aeromonas hydrophila.Antlmicrob Agents Chemother,2007,51(6):2136-2142.
  • [13]Wyrombak PN,Babaogh K,Pelto RB,et al.O-aryloxyearbonyl hydroxamates:new beta-lactamase inhibitors that cross-link the active site.J Am Chem Soc,2007,129(31):9548-9549.
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