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Antimicrobial Agents and Chemotherapy, April 2001, p. 1058-1064, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1058-1064.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Peptide Deformylase as an Antibacterial Drug Target: Target Validation and Resistance Development

Christian M. Apfel,* Hans Locher,dagger Stefan Evers, Béla Takács, Christian Hubschwerlen,dagger Wolfgang Pirson, Malcolm G. P. Page, and Wolfgang Keckdagger

Pharma Research Basel, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland

Received 10 August 2000/Returned for modification 5 October 2000/Accepted 20 December 2000

New inhibitors of peptide deformylase (PDF) which are very potent against the isolated enzyme and show a certain degree of antibacterial activity have recently been synthesized by our group. Several lines of experimental evidence indicate that these inhibitors indeed interfere with the target enzyme in the bacterial cell. (i) The inhibition of Escherichia coli growth could be counteracted by overexpression of PDF from different organisms, including E. coli, Streptococcus pneumoniae, and Haemophilus influenzae. Conversely, reduced expression of PDF in S. pneumoniae resulted in an increased susceptibility to the inhibitors. (ii) Proteome analysis on two-dimensional gels revealed a shift for many proteins towards lower pI in the presence of PDF inhibitors, as would be expected if the proteins still carry their N-formyl-Met terminus. (iii) PDF inhibitors show no antimicrobial activity against E. coli under conditions that make growth independent of formylation and deformylation. The antibacterial activity in E. coli was characterized as bacteriostatic. Furthermore, the development of resistance in E. coli was observed to occur with high frequency (10-7). Resistant mutants show a reduced growth rate, and DNA sequence analysis revealed mutations in their formyl transferase gene. Taking all these aspects into account, we conclude that PDF may not be an optimal target for broad-spectrum antibacterial agents.

* Corresponding author. Mailing address: F. Hoffmann-La Roche Ltd., PRBM-H, Bldg. 69/11A, CH-4070 Basel, Switzerland. Phone: 41 61 688 5878. Fax: 41 61 688 2377. E-mail: christian.apfel{at}roche.com.

dagger Present address: Morphochem AG, Basel, Switzerland.

Antimicrobial Agents and Chemotherapy, April 2001, p. 1058-1064, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1058-1064.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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