Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, USA.
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, USA
mBio. 2017 Oct 31;8(5):e01172-17. doi: 10.1128/mBio.01172-17.
Gram-negative bacteria are notoriously resistant to antibiotics, but the extent of the resistance varies broadly between species. We report that in significant human pathogens , , and spp., the differences in antibiotic resistance are largely defined by their penetration into the cell. For all tested antibiotics, the intracellular penetration was determined by a synergistic relationship between active efflux and the permeability barrier. We found that the outer membrane (OM) and efflux pumps select compounds on the basis of distinct properties and together universally protect bacteria from structurally diverse antibiotics. On the basis of their interactions with the permeability barriers, antibiotics can be divided into four clusters that occupy defined physicochemical spaces. Our results suggest that rules of intracellular penetration are intrinsic to these clusters. The identified specificities in the permeability barriers should help in the designing of successful therapeutic strategies against antibiotic-resistant pathogens. Multidrug-resistant strains of Gram-negative pathogens rapidly spread in clinics. Significant efforts worldwide are currently directed to finding the rules of permeation of antibiotics across two membrane envelopes of these bacteria. This study created the tools for analysis of and identified the major differences in antibacterial activities that distinguish the permeability barriers of , , , and We conclude that synergy between active efflux and the outer membrane barrier universally protects Gram-negative bacteria from antibiotics. We also found that the diversity of antibiotics affected by active efflux and outer membrane barriers is broader than previously thought and that antibiotics cluster according to specific biological determinants such as the requirement of specific porins in the OM, targeting of the OM, or specific recognition by efflux pumps. No universal rules of antibiotic permeation into Gram-negative bacteria apparently exist. Our results suggest that antibiotic clusters are defined by specific rules of permeation and that further studies could lead to their discovery.
革兰氏阴性菌对抗生素具有很强的耐药性，但不同物种之间的耐药程度差异很大。我们报告称，在重要的人类病原体 、 、 和 spp. 中，抗生素耐药性的差异在很大程度上取决于它们进入细胞的程度。对于所有测试的抗生素，细胞内渗透是由主动外排和通透性屏障之间的协同关系决定的。我们发现，外膜 (OM) 和外排泵根据不同的特性选择化合物，共同普遍保护细菌免受结构多样的抗生素的侵害。基于它们与通透性屏障的相互作用，抗生素可以分为四个簇，占据不同的物理化学空间。我们的结果表明，细胞内渗透的规则是这些簇的固有特性。通透性屏障的特定性质有助于设计针对抗药性病原体的成功治疗策略。革兰氏阴性病原体的多药耐药菌株在临床上迅速传播。目前，全世界都在努力寻找抗生素穿透这些细菌双层膜的渗透规则。这项研究为分析革兰氏阴性菌的通透性差异创造了工具，并确定了区分 、 、 和 通透性屏障的主要抗菌活性差异。我们得出的结论是，主动外排和外膜屏障之间的协同作用普遍保护革兰氏阴性菌免受抗生素的侵害。我们还发现，受主动外排和外膜屏障影响的抗生素的多样性比以前认为的更广泛，并且抗生素根据特定的生物学决定因素聚类，例如 OM 中特定孔蛋白的需求、OM 的靶向或外排泵的特定识别。显然，革兰氏阴性菌中抗生素渗透没有普遍的规则。我们的研究结果表明，抗生素簇是由特定的渗透规则定义的，进一步的研究可能会发现这些规则。
