Broad-spectrum antibiotic activity of the arylomycin natural products is masked by natural target mutations.
Broad-spectrum antibiotic activity of the arylomycin natural products is masked by natural target mutations.
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DOI：
10.1016/j.chembiol.2010.09.009
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发表时间：
2010-11-24
影响因子：
--
通讯作者：
Romesberg FE
中科院分区：
文献类型：
--
作者：
Smith PA;Roberts TC;Romesberg FE
需要新型广谱抗生素来治疗多重耐药病原体。芳基霉素类的天然产物抑制一个有前途的抗微生物目标，I型信号肽酶（SPase），但在最初的表征似乎缺乏对大多数病原体的全细胞活性。在这里，我们表明，表皮葡萄球菌，这是敏感的芳霉素，通过SPase的突变和类似的突变是负责金黄色葡萄球菌，大肠杆菌和铜绿假单胞菌的天然耐药性的耐药性演变。我们鉴定了缺乏这些突变的多种细菌，并证明大多数对芳基霉素敏感。结果表明，芳基霉素具有广谱活性，是开发成治疗剂的可行候选物。研究结果还提出了一种可能性，即天然存在的耐药性可能掩盖了其他可能开发成治疗药物的天然产物支架。
Novel classes of broad-spectrum antibiotics are needed to treat multidrug resistant pathogens. The arylomycin class of natural products inhibits a promising antimicrobial target, type I signal peptidase (SPase), but upon initial characterization appeared to lack whole cell activity against most pathogens. Here, we show that Staphylococcus epidermidis, which is sensitive to the arylomycins, evolves resistance via mutations in SPase and that analogous mutations are responsible for the natural resistance of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We identify diverse bacteria lacking these mutations and demonstrate that most are sensitive to the arylomycins. The results illustrate that the arylomycins have a broad-spectrum of activity and are viable candidates for development into therapeutics. The results also raise the possibility that naturally occurring resistance may have masked other natural product scaffolds that might be developed into therapeutics.
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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：
64.8
作者：
Papp, B;Pál, C;Hurst, LD
通讯作者：
Hurst, LD
影响因子：
3.2
作者：
Cregg, KM;Wilding, EI;Black, MT
通讯作者：
Black, MT
影响因子：
4
作者：
Lambert, PA
通讯作者：
Lambert, PA
影响因子：
6.1
作者：
Hammerschlag, Margaret R.;Sharma, Roopali
通讯作者：
Sharma, Roopali