Smith Peter A, Roberts Tucker C, Romesberg Floyd E
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Chem Biol. 2010 Nov 24;17(11):1223-31. doi: 10.1016/j.chembiol.2010.09.009.
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.
治疗多重耐药病原体需要新型广谱抗生素。芳霉素类天然产物可抑制一种有前景的抗菌靶点——I型信号肽酶（SPase），但初步表征显示其对大多数病原体似乎缺乏全细胞活性。在此，我们表明对芳霉素敏感的表皮葡萄球菌通过SPase突变产生耐药性，并且类似的突变导致金黄色葡萄球菌、大肠杆菌和铜绿假单胞菌具有天然耐药性。我们鉴定出缺乏这些突变的多种细菌，并证明大多数对芳霉素敏感。结果表明芳霉素具有广谱活性，是开发成治疗药物的可行候选物。结果还提出一种可能性，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。
