Peptide deformylase inhibitors as potent antimycobacterial agents.
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Teo, Jeanette, Thayalan, Pamela, Beer, David, Yap, Amelia, Nanjundappa, Mahesh, Ngew, Xinyi, Duraiswamy, Jeyaraj, Liung, Sarah, Dartois, Veronique, Schreiber, Mark, Hasan, Samiul, Cynamon, Michael, Ryder, Neil, Yang, Xia, Weidmann, Beat, Bracken, Kathryn, Dick, Thomas and Mukherjee, Kakoli (2006) Peptide deformylase inhibitors as potent antimycobacterial agents. Antimicrobial Agents and Chemotherapy, 50 (11). pp. 3665-3673. ISSN 0066-4804
Abstract
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 microM. Pharmacokinetic studies of potential leads showed that the compounds were orally bioavailable. Spontaneous resistance towards these inhibitors arose at a frequency of < or =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.
| Item Type: | Article |
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| Additional Information: | free final full text version available at publisher's official URL and at PubMedCentral; author can archive post-print (ie final draft post-refereeing); but on personal or university-hosted websites only |
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| Date Deposited: | 14 Dec 2009 14:01 |
| Last Modified: | 31 Jan 2013 01:20 |
| URI: | https://oak.novartis.com/id/eprint/309 |