Structure-activity relationship analysis and therapeutic potential of peptide deformylase inhibitors

Abstract number: 1133_191

Meinnel T., Giglione C., Boularot A., Serero A.

Peptide deformylation is the first step of the N-terminal Met excision (NME) pathway in bacteria, unmasking the N-Met, making possible the action of Met aminopeptidase [1]. Deformylation is a crucial step in bacterial protein biosynthesis and is essential for bacterial growth [2]. At least one PDF gene has been found in all eubacterial genomes sequenced to date [3]. Peptide deformylase inhibitors (PDFI) appear to be one of the most exciting classes of antibacterial agents discovered to date. Rapid progress in the development of PDFI has been possible because (i) PDF is a metalloprotease, and this class of enzymes shows a high degree of structure-function conservation and (ii) the most potent PDFI are hydroxamate derivatives, a well known category of pharmacophores. The current challenge in structure activity relationship analysis is obtaining molecules with potent antibacterial activity in vivo against a range of drug resistant pathogens [4]. The PDFI now in clinical trials target community based bacterial infections, corresponding to a major pharmaceutical market [5]. Nevertheless, a transcribed gene encoding a homolog of bacterial PDF has been identified in the human genome [6]; the encoded enzyme was shown to be active as a PDF in vitro, located in the mitochondria and one of the two components of mitochondrial NME [7–9]. Although further studies are required to determine the precise function of human mitochondrial NME, PDF activity appears to be crucial for human cells growth [10]. In this context, the precautionary principle imposes a new schedule of conditions for the design of new PDFI that will take into account the absence of inhibition of human PDF. As PDF inhibitors seem to have only very low levels of toxicity in human cells, PDF is however truly an exciting new target for the design of novel antibiotics.

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