Bioenergetic suppression by redox-active metabolites promotes antibiotic tolerance in Pseudomonas aeruginosa

生物能学 绿脓素 生物膜 细菌 多药耐受 生物物理学 化学渗透 生物 铜绿假单胞菌 氧化还原 非生物成分 活性氧 化学 生物化学 微生物学 群体感应 ATP合酶 线粒体 生态学 遗传学 有机化学
作者
Richard D. Horak,John A. Ciemniecki,Dianne K. Newman
出处
期刊:Proceedings of the National Academy of Sciences of the United States of America [National Academy of Sciences]
卷期号:121 (46)
标识
DOI:10.1073/pnas.2406555121
摘要

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.
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