Predictive compound accumulation rules yield a broad-spectrum antibiotic.
Predictive compound accumulation rules yield a broad-spectrum antibiotic.
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DOI：
10.1038/nature22308
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发表时间：
2017-05-18
期刊：
影响因子：
64.8
通讯作者：
Hergenrother PJ
中科院分区：
文献类型：
--
作者：
Richter MF;Drown BS;Riley AP;Garcia A;Shirai T;Svec RL;Hergenrother PJ
大多数小分子无法快速穿过革兰氏阴性细菌的外膜并在这些细胞内积累，这使得发现这些病原体急需的药物非常具有挑战性。目前对决定革兰氏阴性中小分子积累的物理化学性质的理解主要基于对抗菌药物的回顾性分析，这些分析表明极性和分子量是关键因素。在这里，我们评估了超过180种不同化合物在大肠杆菌中积累的能力。结果的计算分析揭示了与回顾性研究的主要差异，即最有可能积聚的小分子含有胺，是两亲性和刚性的，并且具有低球形。然后应用这些指南将脱氧霉素（一种仅对革兰氏阳性菌有效的天然产物）转化为一种对多种多重耐药革兰氏阴性病原体具有活性的抗生素。我们期望这些发现将有助于发现和开发对革兰氏阴性菌有效的抗生素。
Most small molecules are unable to rapidly traverse the outer membrane of Gram-negative bacteria and accumulate inside these cells, making the discovery of much-needed drugs for these pathogens very challenging. Current understanding of the physicochemical properties that dictate small-molecule accumulation in Gram-negatives is largely based on retrospective analyses of antibacterials that suggest polarity and molecular weight as key factors. Here we assess the ability of over 180 diverse compounds to accumulate in Escherichia coli. Computational analysis of the results reveals major differences from the retrospective studies, namely that the small molecules that are most likely to accumulate contain an amine, are amphiphilic and rigid, and have low globularity. These guidelines were then applied to convert deoxynybomycin, a natural product that is active only against Gram-positive organisms, into an antibiotic with activity against a diverse panel of multi-drug-resistant Gram-negative pathogens. We anticipate these findings will aid in the discovery and development of antibiotics effective against Gram-negative bacteria.
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影响因子：
4
作者：
Davis, Tony D.;Gerry, Christopher J.;Tan, Derek S.
通讯作者：
Tan, Derek S.
DOI：
10.1126/science.1176667
发表时间：
2009-08-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fischbach MA;Walsh CT
通讯作者：
Walsh CT
影响因子：
--
作者：
BROWN, DM;ACRED, P
通讯作者：
ACRED, P
影响因子：
21.8
作者：
通讯作者：
--
影响因子：
11.8
作者：
Boucher, Helen W.;Talbot, George H.;Bartlett, John
通讯作者：
Bartlett, John