Peptide deformylase inhibitors as potent antimycobacterial agents
Peptide deformylase inhibitors as potent antimycobacterial agents
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DOI：
10.1128/aac.00555-06
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发表时间：
2006-11-01
影响因子：
4.9
通讯作者：
Mukherjee, Kakoli
中科院分区：
文献类型：
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作者：
Teo, Jeanette W. P.;Thayalan, Pamela;Mukherjee, Kakoli
肽去甲酰基酶 (PDF) 催化新生蛋白质 N 末端甲酰基的水解去除。这是细菌蛋白质合成的重要步骤，使 PDF 成为抗菌药物开发的有吸引力的目标。 def 基因编码来自结核分枝杆菌的 PDF，其重要性通过牛分枝杆菌 BCG 的基因敲除实验得到了证明。来自结核分枝杆菌菌株 H37Rv 的 PDF 在大肠杆菌中被克隆、表达和纯化为 N 末端组氨酸标签重组蛋白。合成了一类新型 PDF 抑制剂 (PDF-I)，即 N-烷基脲异羟肟酸，并评估了其对抗结核分枝杆菌 PDF 酶的活性以及抗分枝杆菌作用。新类别中的几种化合物的 50% 抑制浓度 (IC50) 值 < 100 nM。一些 PDF-I 显示出针对结核分枝杆菌的抗菌活性，包括 MIC90 值 < 1 μM 的 MDR 菌株。潜在先导药物的药代动力学研究表明，这些化合物具有口服生物利用度。对这些抑制剂的自发抵抗出现的频率为
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 mu M. Pharmacokinetic studies of potential leads showed that the compounds were orally bioavailable. Spontaneous resistance towards these inhibitors arose at a frequency of