Antibiotic Activity and Characterization of BB-3497, a Novel Peptide Deformylase Inhibitor

doi:10.1128/AAC.45.2.563-570.2001

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Antimicrobial Agents and Chemotherapy, February 2001, p. 563-570, Vol. 45, No. 2
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.2.563-570.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Antibiotic Activity and Characterization of BB-3497, a Novel Peptide Deformylase Inhibitor

John M. Clements,¹^,^* R. Paul Beckett,¹ Anthony Brown,¹ Graham Catlin,¹ Mario Lobell,¹ Shilpa Palan,¹ Wayne Thomas,¹ Mark Whittaker,¹ Stephen Wood,¹ Sameeh Salama,² Patrick J. Baker,³ H. Fiona Rodgers,³ Vladimir Barynin,³ David W. Rice,³ and Michael G. Hunter¹

British Biotech Pharmaceuticals Ltd., Oxford OX4 6LY,¹ and Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN,³ United Kingdom, and Naeja Pharmaceutical, Inc., Edmonton, Alberta T6E 5V2, Canada²

Received 4 August 2000/Returned for modification 28 September 2000/Accepted 26 October 2000

Peptide deformylase (PDF) is an essential bacterial metalloenzyme which deformylates the N-formylmethionine of newly synthesizedpolypeptides and as such represents a novel target for antibacterialchemotherapy. To identify novel PDF inhibitors, we screened ametalloenzyme inhibitor library and identified an N-formyl-hydroxylaminederivative, BB-3497, and a related natural hydroxamic acid antibiotic,actinonin, as potent and selective inhibitors of PDF. To elucidatethe interactions that contribute to the binding affinity of theseinhibitors, we determined the crystal structures of BB-3497 andactinonin bound to Escherichia coli PDF at resolutions of 2.1and 1.75 Å, respectively. In both complexes, the active-sitemetal atom was pentacoordinated by the side chains of Cys 90,His 132, and His 136 and the two oxygen atoms of N-formyl-hydroxylamineor hydroxamate. BB-3497 had activity against gram-positive bacteria,including methicillin-resistant Staphylococcus aureus and vancomycin-resistantEnterococcus faecalis, and activity against some gram-negativebacteria. Time-kill analysis showed that the mode of action ofBB-3497 was primarily bacteriostatic. The mechanism of resistancewas via mutations within the formyltransferase gene, as previouslydescribed for actinonin. While actinonin and its derivatives havenot been used clinically because of their poor pharmacokineticproperties, BB-3497 was shown to be orally bioavailable. A singleoral dose of BB-3497 given 1 h after intraperitoneal injectionof S. aureus Smith or methicillin-resistant S. aureus protectedmice from infection with median effective doses of 8 and 14 mg/kgof body weight, respectively. These data validate PDF as a noveltarget for the design of a new generation of antibacterialagents.

^* Corresponding author. Mailing address: British Biotech Pharmaceuticals Ltd., Watlington Rd., Oxford OX4 6LY, United Kingdom.Phone: 44 1865 748747. Fax: 44 1865 781034. E-mail: clements{at}britbio.co.uk

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