Resveratrol has been extensively studied due to its potential health benefits in multiple diseases, for example, cancer, obesity and cardiovascular diseases. Besides these properties, resveratrol displays inhibitory activity against a wide range of bacterial species; however, the cellular effects of resveratrol in bacteria remain incompletely understood, especially in the human pathogen, Staphylococcus aureus. In this study, we aimed to identify intrinsic resistance genes that aid S. aureus in tolerating the activity of resveratrol. We screened the Nebraska Transposon Mutant Library, consisting of 1920 mutants with inactivation of non-essential genes in S. aureus JE2, for increased susceptibly to resveratrol. On agar plates containing 0.5× the minimum inhibitory concentration (MIC), 17 transposon mutants failed to grow. Of these, four mutants showed a two-fold reduction in MIC, being the clpP protease mutant and three mutants with deficiencies in the electron transport chain (menD, hemB, aroC). The remaining 13 mutants did not show a reduction in MIC, but were confirmed by spot-assays to have increased susceptibility to resveratrol. Several genes were associated with DNA damage repair (recJ, xerC and xseA). Treatment of S. aureus JE2 with sub-inhibitory concentrations of resveratrol did not affect the expression of recJ, xerC and xseA, but increased expression of the SOS–stress response genes lexA and recA, suggesting that resveratrol interferes with DNA integrity in S. aureus. Expression of error-prone DNA polymerases are part of the SOS–stress response and we could show that sub-inhibitory concentrations of resveratrol increased overall mutation frequency as measured by formation of rifampicin resistant mutants. Our data show that DNA repair systems are important determinants aiding S. aureus to overcome the inhibitory activity of resveratrol. Activation of the SOS response by resveratrol could potentially facilitate the development of resistance towards conventional antibiotics in S. aureus.

中文翻译：

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金黄色葡萄球菌中白藜芦醇内在决定因子的全基因组鉴定

白藜芦醇由于其对多种疾病的潜在健康益处而被广泛研究，例如癌症，肥胖症和心血管疾病。除这些特性外，白藜芦醇还表现出对多种细菌的抑制活性。然而，白藜芦醇在细菌中的细胞作用仍未完全了解，特别是在人类病原体金黄色葡萄球菌中。在这项研究中，我们旨在鉴定有助于金黄色葡萄球菌耐受白藜芦醇活性的内在抗性基因。我们筛选了内布拉斯加转座子突变体文库，该文库由1920个金黄色葡萄球菌中非必需基因失活的突变体组成JE2，对白藜芦醇敏感。在含有最小抑菌浓度（MIC）0.5的琼脂平板上，17个转座子突变体无法生长。其中，四个突变体的MIC降低了两倍，是clpP蛋白酶突变体，三个突变体的电子传输链（menD，hemB，aroC）缺乏。其余的13个突变体未显示MIC降低，但通过点检证实对白藜芦醇的敏感性增加。几个基因与DNA损伤修复有关（recJ，xerC和xseA）。金黄色葡萄球菌的治疗具有亚抑制浓度白藜芦醇的JE2不会影响recJ，xerC和xseA的表达，但是会增加SOS应激反应基因lexA和recA的表达，这表明白藜芦醇会干扰金黄色葡萄球菌的DNA完整性。容易出错的DNA聚合酶的表达是SOS应激反应的一部分，我们可以证明白藜芦醇的亚抑制浓度增加了利福平抗性突变体形成的总体突变频率。我们的数据表明DNA修复系统是帮助金黄色葡萄球菌的重要决定因素克服白藜芦醇的抑制活性。白藜芦醇激活SOS反应可能促进金黄色葡萄球菌对常规抗生素的抗药性的发展。