Structural study of phenyl boronic acid derivatives as AmpC beta-lactamase inhibitors.

A small set of boronic acids acting as low nanomolar inhibitors of AmpC beta-lactamase were designed and synthesized in the effort to improve affinity, pharmacokinetic properties, and to provide a valid lead compound. X-ray crystallography revealed the binary complex of the best inhibitor bound to the enzyme, highlighting possibilities for its further rational derivatization and chemical optimization.

[1]  G S Weston,et al.  Three-dimensional structure of AmpC beta-lactamase from Escherichia coli bound to a transition-state analogue: possible implications for the oxyanion hypothesis and for inhibitor design. , 1998, Biochemistry.

[2]  Yun Zhang,et al.  Molecular dynamics at the root of expansion of function in the M69L inhibitor-resistant TEM beta-lactamase from Escherichia coli. , 2002, Journal of the American Chemical Society.

[3]  R. Bonomo,et al.  Probing active site chemistry in SHV beta-lactamase variants at Ambler position 244. Understanding unique properties of inhibitor resistance. , 2006, The Journal of biological chemistry.

[4]  R. Bonomo,et al.  Inhibitor-resistant class A beta-lactamases: consequences of the Ser130-to-Gly mutation seen in Apo and tazobactam structures of the SHV-1 variant. , 2004, Biochemistry.

[5]  B. Shoichet,et al.  Crystal Structures of Substrate and Inhibitor Complexes with AmpC β-Lactamase: Possible Implications for Substrate-Assisted Catalysis , 2000 .

[6]  T. Sawai,et al.  Structure of the extended-spectrum class C beta-lactamase of Enterobacter cloacae GC1, a natural mutant with a tandem tripeptide insertion. , 1999, Biochemistry.

[7]  S. Essack,et al.  The Development of β-Lactam Antibiotics in Response to the Evolution of β-Lactamases , 2001, Pharmaceutical Research.

[8]  A. Dubus,et al.  The role of tyrosine 150 in catalysis of beta-lactam hydrolysis by AmpC beta-lactamase from Escherichia coli investigated by site-directed mutagenesis. , 1994, Biochemistry.

[9]  Cooperative evolution of mechanisms of β‐lactam resistance , 2000 .

[10]  R. Bonomo,et al.  Use of Novel Boronic Acid Transition State Inhibitors To Probe Substrate Affinity in SHV-Type Extended-Spectrum β-Lactamases , 2007, Antimicrobial Agents and Chemotherapy.

[11]  George A. Jacoby,et al.  Plasmid-Determined AmpC-Type β-Lactamases , 2002, Antimicrobial Agents and Chemotherapy.

[12]  P. Bradford.  Extended-Spectrum β-Lactamases in the 21st Century: Characterization, Epidemiology, and Detection of This Important Resistance Threat , 2001, Clinical Microbiology Reviews.

[13]  Brian K Shoichet,et al.  Structure-based approach for binding site identification on AmpC beta-lactamase. , 2002, Journal of medicinal chemistry.

[14]  G S Weston,et al.  Structure-based enhancement of boronic acid-based inhibitors of AmpC beta-lactamase. , 1998, Journal of medicinal chemistry.

[15]  Maria Paola Costi,et al.  Structure-based design and in-parallel synthesis of inhibitors of AmpC β-lactamase , 2001 .

[16]  J. Frère,et al.  Cytosolic Intermediates for Cell Wall Biosynthesis and Degradation Control Inducible β-Lactam Resistance in Gram-Negative Bacteria , 1997, Cell.

[17]  Jesús Blázquez,et al.  The complexed structure and antimicrobial activity of a non‐β‐lactam inhibitor of AmpC β‐lactamase , 2008, Protein science : a publication of the Protein Society.