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Current Drug Targets - Infectious Disorders

Editor-in-Chief

ISSN (Print): 1568-0053
ISSN (Online): 1875-5852

PDF Inhibitors: An Emerging Class of Antibacterial Drugs

Author(s): K. W. Johnson, D. Lofland and H. E. Moser

Volume 5, Issue 1, 2005

Page: [39 - 52] Pages: 14

DOI: 10.2174/1568005053174618

Price: $65

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Abstract

The metalloenzyme peptide deformylase (PDF) represents one of the most promising bacterial targets in the search for novel mode of action antibiotics that lack cross-resistance to existing drugs. Initial research and clinical development has focused on anti-pneumococcal applications. During optimization, peptide analogs were developed containing either a hydroxamate or formyl-hydroxylamine as metal interacting group, yielding inhibitors with in vitro activity against a broad spectrum of organisms. Preclinical studies revealed potent antibacterial activity in vivo that is paired with good pharmacokinetic properties and excellent tolerability in different species. BB-83698, a potent PDF inhibitor with i.v. and oral efficacy in preclinical animal models, represents the first class-representative compound evaluated in man. The inhibitor was administered by i.v. infusion and was shown to exhibit generally dose-proportional pharmacokinetics. It was well tolerated up to doses providing predicted therapeutic exposures. These human results, combined with the preclinical information, clearly support the potential of PDF inhibitors for development as a novel class of antibacterial therapeutics.

Keywords: peptide deformylase, review, antibiotics, enzyme inhibitor, peptide analogs, pharmacology, pharmacokinetics


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