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

• 成果类型: Article
• 署名作者: Horak, Richard D.; Ciemniecki, John A.; Newman, Dianne K.
• 署名单位: California Institute of Technology; California Institute of Technology
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8559
• DOI: 10.1073/pnas.2406555121
• 发表日期: 2024-11-12
• 关键词: hydrogen-peroxide; pyocyanin; Heterogeneity; ACID; responses; biofilms; GROWTH; roles; cells; flux

摘要

The proton- motive force (PMF), consisting of a pH gradient and a membrane potential (Delta Psi) 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 (O2). Under oxic conditions, the phenazines pyocyanin and phenazine- 1- carboximide, as well as toxoflavin-a RAM produced by Burkholderia species-suppress the Delta Psi 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 Delta Psi 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 O2; it can be reversed by increasing the Delta Psi 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.