The proton-motive force (PMF), consisting of a pH gradient and a membrane potential (ΔΨ) underpins many processes essential to bacterial growth and/or survival. Yet bacteria often enter a bioenergetically diminished state characterized by a low PMF. Consequently, they have increased tolerance for diverse stressors, including clinical antibiotics. Despite the ubiquity of low metabolic rates in the environment, the extent to which bacteria have agency over entry into such a low-bioenergetic state has received relatively little attention. Here, we tested the hypothesis that production of redox-active metabolites (RAMs) could drive such a physiological transition. Pseudomonas aeruginosa is an opportunistic pathogen that produces phenazines, model RAMs that are highly toxic in the presence of molecular oxygen (O 2 ). Under oxic conditions, the phenazines pyocyanin and phenazine-1-carboximide, as well as toxoflavin—a RAM produced by Burkholderia species—suppress the ΔΨ in distinct ways across distributions of single cells, reduce the efficiency of proton pumping, and lower cellular adenosine-triphosphate (ATP) levels. In planktonic culture, the degree and rate by which each RAM lowers the ΔΨ correlates with the protection it confers against antibiotics that strongly impact cellular energy flux. This bioenergetic suppression requires the RAM’s presence and corresponds to its cellular reduction rate and abiotic oxidation rate by O 2 ; it can be reversed by increasing the ΔΨ with nigericin. RAMs similarly impact the bioenergetic state of cells in (hyp)oxic biofilm aggregates. Collectively, these findings demonstrate that bacteria can suppress their bioenergetic state by the production of endogenous toxins in a manner that bolsters stress resilience.

中文翻译：

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氧化还原活性代谢物的生物能量抑制促进了铜绿假单胞菌的抗生素耐受性


质子动力 （PMF） 由 pH 梯度和膜电位 （ΔΨ） 组成，是细菌生长和/或生存所必需的许多过程的基础。然而，细菌经常进入以低 PMF 为特征的生物能量减弱状态。因此，他们对包括临床抗生素在内的各种压力源的耐受性增加。尽管环境中普遍存在低代谢率，但细菌在多大程度上对进入这种低生物能量状态具有代理作用，但受到的关注相对较少。在这里，我们检验了氧化还原活性代谢物 （RAMs） 的产生可以驱动这种生理转变的假设。铜绿假单胞菌是一种机会性病原体，可产生苯嗪，苯嗪模型 RAM，在分子氧 （O 2） 存在下具有剧毒。在含氧条件下，吩嗪绿脓素和吩嗪-1-羧酰亚胺，以及弓黄素（一种由伯克霍尔德氏菌属产生的 RAM）在单细胞分布中以不同的方式抑制 ΔΨ，降低质子泵送的效率，并降低细胞三磷酸腺苷 （ATP） 水平。在浮游生物培养中，每个 RAM 降低 ΔΨ 的程度和速率与它对强烈影响细胞能量通量的抗生素的保护相关。这种生物能量抑制需要 RAM 的存在，并对应于其细胞还原率和非生物氧化率 O 2 ;可以通过用黑牙菌素增加 ΔΨ 来逆转它。RAM 同样影响 （hyp）oxic 生物膜聚集体中细胞的生物能量状态。总的来说，这些发现表明，细菌可以通过产生内源性毒素来抑制其生物能量状态，从而增强压力恢复力。