Platensimycin activity against mycobacterial beta-ketoacyl-ACP synthases.
Platensimycin activity against mycobacterial beta-ketoacyl-ACP synthases.
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DOI：
10.1371/journal.pone.0006306
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发表时间：
2009-07-17
期刊：
影响因子：
3.7
通讯作者：
Besra GS
中科院分区：
文献类型：
--
作者：
Brown AK;Taylor RC;Bhatt A;Fütterer K;Besra GS
特别是由于最近出现了多重耐药和广泛耐药菌株，迫切需要发现和开发针对结核病病原体结核分枝杆菌的新药。在此，我们检查了分枝杆菌对天然产物平板霉素的敏感性。我们已经证明，platensimycin 对快速生长的耻垢分枝杆菌 (MIC = 14 µg/ml) 和结核分枝杆菌 (MIC = 12 µg/ml) 具有抑菌活性。在帕滕霉素存在下的生长特异性地抑制分枝菌酸的生物合成，这表明抗生素靶向分枝菌酸生物合成复合物的成分。鉴于platensimycin对来自金黄色葡萄球菌的β-酮脂酰-ACP合酶的抑制活性，结核分枝杆菌KasA、KasB或FabH在耻垢分枝杆菌中过度表达，以确定这些分枝杆菌KAS酶是否是platensimycin的靶标。在耻垢分枝杆菌中，kasA 或 kasB 的过度表达使菌株的 MIC 分别从 14 µg/ml 增加至 30 和 124 µg/ml。然而，fabH on 的过度表达并不影响 MIC。此外，与过表达数据一致，使用纯化蛋白的体外测定表明，平板霉素抑制 Mt-KasA 和 Mt-KasB，但不抑制 Mt-FabH。我们的结果表明，platensimycin 对分枝杆菌 KasA 和 KasB 具有活性，因此是一种令人兴奋的抗结核分枝杆菌先导化合物，也是新合成类似物开发的一个令人兴奋的先导化合物。
There is an urgent need for the discovery and development of new drugs against Mycobacterium tuberculosis, the causative agent of tuberculosis, especially due to the recent emergence of multi-drug and extensively-drug resistant strains. Herein, we have examined the susceptibility of mycobacteria to the natural product platensimycin. We have demonstrated that platensimycin has bacteriostatic activity against the fast growing Mycobacterium smegmatis (MIC = 14 µg/ml) and against Mycobacterium tuberculosis (MIC = 12 µg/ml). Growth in the presence of paltensimycin specifically inhibited the biosynthesis of mycolic acids suggesting that the antibiotic targeted the components of the mycolate biosynthesis complex. Given the inhibitory activity of platensimycin against β-ketoacyl-ACP synthases from Staphylococcus aureus, M. tuberculosis KasA, KasB or FabH were overexpressed in M. smegmatis to establish whether these mycobacterial KAS enzymes were targets of platensimycin. In M. smegmatis overexpression of kasA or kasB increased the MIC of the strains from 14 µg/ml, to 30 and 124 µg/ml respectively. However, overexpression of fabH on did not affect the MIC. Additionally, consistent with the overexpression data, in vitro assays using purified proteins demonstrated that platensimycin inhibited Mt-KasA and Mt-KasB, but not Mt-FabH. Our results have shown that platensimycin is active against mycobacterial KasA and KasB and is thus an exciting lead compound against M. tuberculosis and the development of new synthetic analogues.
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影响因子：
3.2
作者：
Bhatt, A;Kremer, L;Jacobs, WR
通讯作者：
Jacobs, WR
影响因子：
2.8
作者：
Bardarov, S;Bardarov, S;Jacobs, WR
通讯作者：
Jacobs, WR
影响因子：
2.8
作者：
Brown, Alistair K.;Papaemmanouil, Athina;Besra, Gurdyal S.
通讯作者：
Besra, Gurdyal S.
影响因子：
3.6
作者：
Larsen, MH;Vilchèze, C;Jacobs, WR
通讯作者：
Jacobs, WR
影响因子：
4.8
作者：
Brown, AK;Sridharan, S;Besra, GS
通讯作者：
Besra, GS