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Antimicrobial Agents and Chemotherapy, November 2006, p. 3665-3673, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00555-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Peptide Deformylase Inhibitors as Potent Antimycobacterial Agents ^,

Jeanette W. P. Teo,^1, Pamela Thayalan,¹ David Beer,¹ Amelia S. L. Yap,¹ Mahesh Nanjundappa,¹ Xinyi Ngew,¹ Jeyaraj Duraiswamy,¹ Sarah Liung,¹ Veronique Dartois,¹ Mark Schreiber,¹ Samiul Hasan,¹ Michael Cynamon,² Neil S. Ryder,³ Xia Yang,³ Beat Weidmann,³ Kathryn Bracken,³ Thomas Dick,¹ and Kakoli Mukherjee^1*

Novartis Institute for Tropical Diseases, 10 Biopolis Road, 05-01 Chromos, Singapore 138670, Republic of Singapore,¹ Central New York Research Corporation, New York, New York,² Novartis Institutes for Biomedical Research, Inc., Infectious Disease Area, 100 Technology Square, Cambridge, Massachusetts 02139³

Received 4 May 2006/ Returned for modification 6 June 2006/ Accepted 17 August 2006

Peptide deformylase (PDF) catalyzes the hydrolytic removal of the N-terminal formyl group from nascent proteins. This is an essential step in bacterial protein synthesis, making PDF an attractive target for antibacterial drug development. Essentiality of the def gene, encoding PDF from Mycobacterium tuberculosis, was demonstrated through genetic knockout experiments with Mycobacterium bovis BCG. PDF from M. tuberculosis strain H37Rv was cloned, expressed, and purified as an N-terminal histidine-tagged recombinant protein in Escherichia coli. A novel class of PDF inhibitors (PDF-I), the N-alkyl urea hydroxamic acids, were synthesized and evaluated for their activities against the M. tuberculosis PDF enzyme as well as their antimycobacterial effects. Several compounds from the new class had 50% inhibitory concentration (IC₅₀) values of <100 nM. Some of the PDF-I displayed antibacterial activity against M. tuberculosis, including MDR strains with MIC₉₀ values of <1 µM. Pharmacokinetic studies of potential leads showed that the compounds were orally bioavailable. Spontaneous resistance towards these inhibitors arose at a frequency of 5 x 10^–7 in M. bovis BCG. DNA sequence analysis of several spontaneous PDF-I-resistant mutants revealed that half of the mutants had acquired point mutations in their formyl methyltransferase gene (fmt), which formylated Met-tRNA. The results from this study validate M. tuberculosis PDF as a drug target and suggest that this class of compounds have the potential to be developed as novel antimycobacterial agents.

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* Corresponding author. Mailing address: Novartis Institute for Tropical Diseases, 10 Biopolis Road, 05-01 Chromos, Singapore 138670, Republic of Singapore. Phone: 65-67222923. Fax: 65-67222917. E-mail: kakoli.mukherjee{at}novartis.com.

Published ahead of print on 11 September 2006.

Supplemental material for this article may be found at http://aac.asm.org/.

Present address: National University Hospital, Department of Laboratory Medicine, 5 Lower Kent Ridge Road, Main Building, Level 3, Singapore 119 074, Republic of Singapore.

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Antimicrobial Agents and Chemotherapy, November 2006, p. 3665-3673, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00555-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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