Bicarbonate Alters Bacterial Susceptibility to Antibiotics by Targeting the Proton Motive Force
Bicarbonate Alters Bacterial Susceptibility to Antibiotics by Targeting the Proton Motive Force
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DOI：
10.1021/acsinfecdis.7b00194
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发表时间：
2018-03-01
影响因子：
5.3
通讯作者：
Brown, Eric D.
中科院分区：
文献类型：
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作者：
Farha, Maya A.;French, Shawn;Brown, Eric D.
碳酸氢钠的抗菌性能早在多年前就已为人所知，但对其作用机制的分子机制仍缺乏了解。利用化学组合的方法，我们首先探索了碳酸氢钠对常规抗生素活性的影响，以推测其作用机制。值得注意的是，在这种无处不在的缓冲液的存在下，8类抗生素的活性不同。这些相互作用和对作用机制的研究表明，在生理浓度下，碳酸氢盐是跨革兰氏阴性和革兰氏阳性细菌细胞膜的质子驱动力的pH梯度的选择性耗散器。此外，尽管构成先天免疫的成分已经被广泛研究，但从未有人将其与细胞外液中的主要缓冲物质重碳酸盐联系起来。在这里，我们还探讨了碳酸氢盐对天然免疫成分的影响。虽然免疫反应和缓冲系统在体内有不同的功能，但我们假设它们之间存在相互作用，因为生理浓度的碳酸氢盐增强了天然免疫的几个组成部分的抗菌特性。我们的发现表明，在防御病原体的过程中，碳酸氢盐是一种被忽视的宿主免疫增强剂。总体而言，碳酸氢盐独特的作用机制对天然免疫成分和抗生素的活性具有深远和可预见的影响。我们得出结论，小苏打作为抗生素佐剂具有显着的效力，并表明通过利用更好地反映小苏打的生理浓度的测试范式，在发现和开发新的抗菌药物方面具有巨大的潜力。
The antibacterial properties of sodium bicarbonate have been known for years, yet the molecular understanding of its mechanism of action is still lacking. Utilizing chemical chemical combinations, we first explored the effect of bicarbonate on the activity of conventional antibiotics to infer on the mechanism. Remarkably, the activity of 8 classes of antibiotics differed in the presence of this ubiquitous buffer. These interactions and a study of mechanism of action revealed that, at physiological concentrations, bicarbonate is a selective dissipater of the pH gradient of the proton motive force across the cytoplasmic membrane of both Gram-negative and Gram-positive bacteria. Further, while components that make up innate immunity have been extensively studied, a link to bicarbonate, the dominant buffer in the extracellular fluid, has never been made. Here, we also explored the effects of bicarbonate on components of innate immunity. Although the immune response and the buffering system have distinct functions in the body, we posit there is interplay between these, as the antimicrobial properties of several components of innate immunity were enhanced by a physiological concentration of bicarbonate. Our findings implicate bicarbonate as an overlooked potentiator of host immunity in the defense against pathogens. Overall, the unique mechanism of action of bicarbonate has far-reaching and predictable effects on the activity of innate immune components and antibiotics. We conclude that bicarbonate has remarkable power as an antibiotic adjuvant and suggest that there is great potential to exploit this activity in the discovery and development of new antibacterial drugs by leveraging testing paradigms that better reflect the physiological concentration of bicarbonate.