Disruption of the outer membrane (OM) barrier allows for the entry of otherwise inactive antimicrobials into Gram-negative pathogens. Numerous efforts to implement this approach have identified a large number of OM perturbants that sensitize Gram-negative bacteria to many clinically available Gram-positive active antibiotics. However, there is a dearth of investigation into the strengths and limitations of this therapeutic strategy, with an overwhelming focus on characterization of individual potentiator molecules. Herein, we look to explore the utility of exploiting OM perturbation to sensitize Gram-negative pathogens to otherwise inactive antimicrobials. We identify the ability of OM disruption to change the rules of Gram-negative entry, overcome preexisting and spontaneous resistance, and impact biofilm formation. Disruption of the OM expands the threshold of hydrophobicity compatible with Gram-negative activity to include hydrophobic molecules. We demonstrate that while resistance to Gram-positive active antibiotics is surprisingly common in Gram-negative pathogens, OM perturbation overcomes many antibiotic inactivation determinants. Further, we find that OM perturbation reduces the rate of spontaneous resistance to rifampicin and impairs biofilm formation. Together, these data suggest that OM disruption overcomes many of the traditional hurdles encountered during antibiotic treatment and is a high priority approach for further development.

中文翻译：

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外膜破坏克服了固有的，获得性和自发的抗生素抗性。

外膜（OM）屏障的破坏使原本没有活性的抗菌剂进入革兰氏阴性病原体。为实施此方法进行了许多努力，已发现大量的OM扰动剂，它们使革兰氏阴性细菌对许多临床上可用的革兰氏阳性活性抗生素敏感。然而，缺乏对这种治疗策略的优点和局限性的研究，而对单个增强剂分子的表征的关注却是绝大多数。在本文中，我们寻求探索利用OM扰动使革兰氏阴性病原体对原本没有活性的抗菌剂敏感的实用程序。我们确定OM破坏能力来改变革兰氏阴性进入的规则，克服预先存在和自发的抵抗力，并影响生物膜的形成。OM的破坏扩大了与革兰氏阴性活性相容的疏水性阈值，以包括疏水性分子。我们证明虽然对革兰氏阳性活性抗生素的耐药性在革兰氏阴性病原体中出奇地常见，但OM扰动​​克服了许多抗生素失活的决定因素。此外，我们发现OM扰动降低了对利福平的自发抵抗率并损害了生物膜的形成。总之，这些数据表明，OM破坏克服了抗生素治疗期间遇到的许多传统障碍，并且是进一步开发的高度优先方法。我们证明虽然对革兰氏阳性活性抗生素的耐药性在革兰氏阴性病原体中出奇地常见，但OM扰动​​克服了许多抗生素失活的决定因素。此外，我们发现OM扰动降低了对利福平的自发抵抗率并损害了生物膜的形成。总之，这些数据表明，OM破坏克服了抗生素治疗期间遇到的许多传统障碍，并且是进一步开发的高度优先方法。我们证明虽然对革兰氏阳性活性抗生素的耐药性在革兰氏阴性病原体中出奇地常见，但OM扰动​​克服了许多抗生素失活的决定因素。此外，我们发现OM扰动降低了对利福平的自发抵抗率并损害了生物膜的形成。总之，这些数据表明，OM破坏克服了抗生素治疗期间遇到的许多传统障碍，并且是进一步开发的高度优先方法。