Department of Chemistry, Scripps Research Institute, La Jolla, California, USA.
Antimicrob Agents Chemother. 2012 Oct;56(10):5054-60. doi: 10.1128/AAC.00785-12. Epub 2012 Jul 16.
Clinically approved antibiotics inhibit only a small number of conserved pathways that are essential for bacterial viability, and the physiological effects of inhibiting these pathways have been studied in great detail. Likewise, characterizing the effects of candidate antibiotics that function via novel mechanisms of action is critical for their development, which is of increasing importance due to the ever-growing problem of resistance. The arylomycins are a novel class of natural-product antibiotics that act via the inhibition of type I signal peptidase (SPase), which is an essential enzyme that functions as part of the general secretory pathway and is not the target of any clinically deployed antibiotic. Correspondingly, little is known about the effects of SPase inhibition or how bacteria may respond to mitigate the associated secretion stress. Using genetically sensitized Escherichia coli and Staphylococcus aureus as model organisms, we examine the activity of arylomycin as a function of its concentration, bacterial cell density, target expression levels, and bacterial growth phase. The results reveal that the activity of the arylomycins results from an insufficient flux of proteins through the secretion pathway and the resulting mislocalization of proteins. Interestingly, this has profoundly different effects on E. coli and S. aureus. Finally, we examine the activity of arylomycin in combination with distinct classes of antibiotics and demonstrate that SPase inhibition results in synergistic sensitivity when combined with an aminoglycoside.
临床上批准的抗生素仅抑制少数对细菌生存至关重要的保守途径，并且这些途径的抑制的生理效应已经被详细研究过了。同样，表征通过新型作用机制发挥作用的候选抗生素的作用对于它们的开发至关重要，由于耐药性问题日益严重，抗生素的开发变得越来越重要。芳基霉素是一类新型的天然产物抗生素，通过抑制 I 型信号肽酶（SPase）发挥作用，SPase 是一种必需的酶，作为一般分泌途径的一部分发挥作用，不是任何临床应用的抗生素的靶标。相应地，人们对 SPase 抑制的影响或细菌如何应对减轻相关分泌应激知之甚少。我们使用遗传敏感的大肠杆菌和金黄色葡萄球菌作为模型生物，研究了芳基霉素的活性作为其浓度、细菌细胞密度、靶标表达水平和细菌生长阶段的函数。结果表明，芳基霉素的活性源于蛋白质通过分泌途径的通量不足以及蛋白质的定位错误。有趣的是，这对大肠杆菌和金黄色葡萄球菌有截然不同的影响。最后，我们研究了芳基霉素与不同类别的抗生素联合使用的活性，并证明 SPase 抑制与氨基糖苷类药物联合使用时会导致协同敏感性。
