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

Autor: Horak RD; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125., Ciemniecki JA; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125., Newman DK; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.; Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, CA 91125.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Nov 12; Vol. 121 (46), pp. e2406555121. Date of Electronic Publication: 2024 Nov 06.
DOI: 10.1073/pnas.2406555121
Abstrakt: 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.
Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze: MEDLINE
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