Initial efforts toward the optimization of arylomycins for antibiotic activity.
Initial efforts toward the optimization of arylomycins for antibiotic activity.
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DOI：
10.1021/jm1016126
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发表时间：
2011-07-28
影响因子：
7.3
通讯作者：
Romesberg FE
中科院分区：
文献类型：
--
作者：
Roberts TC;Schallenberger MA;Liu J;Smith PA;Romesberg FE
虽然大多数临床使用的抗生素来源于天然产物，但新的广谱天然产物的分离变得越来越罕见，并且窄谱剂通常被认为由于其支架或靶标的内在限制而不适合开发。然而，天然产物抗生素的谱可能受到某些细菌中特定耐药机制的限制，例如靶向突变，并且这种“潜伏”抗生素的谱可能通过衍生化重新优化，就像临床部署的抗生素一样。我们最近表明，芳霉素天然产物抗生素的光谱，其通过抑制I型信号肽酶的新机制发挥作用，比以前认为的更广泛，并且在几种关键的人类病原体中的耐药性是由于靶肽酶中存在特定的Pro残基，其破坏了与抗生素脂肽尾的相互作用。为了开始测试这种天然抗性是否可以通过衍生化来克服，我们合成了具有改变的脂肽尾部的类似物，并鉴定了几种具有增加的抗S.金黄色。数据支持的假设，即芳基霉素是潜在的抗生素，表明它们的光谱可以通过衍生化进行优化，并确定一个有前途的支架上，未来的优化工作可能会集中。
While most clinically used antibiotics were derived from natural products, the isolation of new broad-spectrum natural products has become increasingly rare and narrow-spectrum agents are typically deemed unsuitable for development due to intrinsic limitations of their scaffold or target. However, it is possible that the spectrum of a natural product antibiotic might be limited by specific resistance mechanisms in some bacteria, such as target mutations, and the spectra of such “latent” antibiotics might be re-optimized by derivatization, just as has been done with clinically deployed antibiotics. We recently showed that the spectrum of the arylomycin natural product antibiotics, which act via the novel mechanism of inhibiting type I signal peptidase, is broader than previously believed, and that resistance in several key human pathogens is due to the presence of a specific Pro residue in the target peptidase that disrupts interactions with the lipopeptide tail of the antibiotic. To begin to test whether this natural resistance might be overcome by derivatization, we synthesized analogs with altered lipopeptide tails and identified several with an increased spectrum of activity against S. aureus. The data support the hypothesis that the arylomycins are latent antibiotics, suggest that their spectrum may be optimized by derivatization, and identify a promising scaffold upon which future optimization efforts might focus.
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影响因子：
3.2
作者：
DESIERVO, AJ
通讯作者：
DESIERVO, AJ
影响因子：
3.3
作者：
Allen, NE;LeTourneau, DL;Hobbs, JN
通讯作者：
Hobbs, JN
影响因子：
15
作者：
Chen, L;Yuan, YQ;Walker, S
通讯作者：
Walker, S
DOI：
10.1007/s10295-005-0077-9
发表时间：
2006-07-01
影响因子：
3.4
作者：
Baltz, Richard H.
通讯作者：
Baltz, Richard H.
影响因子：
15
作者：
Kerns, R;Dong, SD;Kahne, D
通讯作者：
Kahne, D