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Antimicrobial Agents and Chemotherapy, December 2001, p. 3279-3286, Vol. 45, No. 12
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.12.3279-3286.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Binding Properties of a Peptide Derived from beta -Lactamase Inhibitory Protein

Gary W. Rudgers,1 Wanzhi Huang,1 and Timothy Palzkill1,2,*

Department of Molecular Virology & Microbiology1 and Department of Biochemistry,2 Baylor College of Medicine, Houston, Texas 77030

Received 28 February 2001/Returned for modification 11 July 2001/Accepted 29 August 2001

To overcome the antibiotic resistance mechanism mediated by beta -lactamases, small-molecule beta -lactamase inhibitors, such as clavulanic acid, have been used. This approach, however, has applied selective pressure for mutations that result in beta -lactamases no longer sensitive to beta -lactamase inhibitors. On the basis of the structure of beta -lactamase inhibitor protein (BLIP), novel peptide inhibitors of beta -lactamase have been constructed. BLIP is a 165-amino-acid protein that is a potent inhibitor of TEM-1 beta -lactamase (Ki = 0.3 nM). The cocrystal structure of TEM-1 beta -lactamase and BLIP indicates that residues 46 to 51 of BLIP make critical interactions with the active site of TEM-1 beta -lactamase. A peptide containing this six-residue region of BLIP was found to retain sufficient binding energy to interact with TEM-1 beta -lactamase. Inhibition assays with the BLIP peptide reveal that, in addition to inhibiting TEM-1 beta -lactamase, the peptide also inhibits a class A beta -lactamase and a class C beta -lactamase that are not inhibited by BLIP. The crystal structures of class A and C beta -lactamases and two penicillin-binding proteins (PBPs) reveal that the enzymes have similar three-dimensional structures in the vicinity of the active site. This similarity suggests that the BLIP peptide inhibitor may have a broad range of activity that can be used to develop novel small-molecule inhibitors of various classes of beta -lactamases and PBPs.

* Corresponding author. Mailing address: Department of Molecular Virology & Microbiology, Baylor College of Medicine, One Baylor Plaza, BCMD Rm. 221D, Mailstop BCM-280, Houston, TX 77030-3498. Phone: (713) 798-5609. Fax: (713) 798-7375. E-mail: timothyp{at}bcm.tmc.edu.

Antimicrobial Agents and Chemotherapy, December 2001, p. 3279-3286, Vol. 45, No. 12
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.12.3279-3286.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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