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High-throughput Screening of Chemical Compounds to Elucidate Their Effects on Bacterial Persistence
Published on: February 23, 2021
A switch in the poly(dC)/RmlB complex regulates bacterial persister formation
Xu Chen1, Gen Li1, Xuewei Liao2
1Soil Ecology Lab, College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, China.
Abstract:
Bacterial persisters are phenotypic variants that tolerate exposure to lethal antibiotics. These dormant cells are responsible for chronic and recurrent infections. Multiple mechanisms have been linked to persister formation. Here, we report that a complex, consisting of an extracellular poly(dC) and its membrane-associated binding protein RmlB, appears to be associated with persistence of the opportunistic pathogen Pseudomonas aeruginosa. Environmental stimuli triggers a switch in the complex physiological state (from poly(dC)/RmlB to P-poly(dC)/RmlB or RmlB). In response to the switch, bacteria decrease proton motive force and intracellular ATP levels, forming dormant cells. This alteration in complex status is linked to a (p)ppGpp-controlled signaling pathway that includes inorganic polyphosphate, Lon protease, exonuclease VII (XseA/XseB), and the type III secretion system. The persistence might be also an adaptive response to the lethal action of the dTDP-L-rhamnose pathway shutdown, which occurs due to switching of poly(dC)/RmlB.
Insights
Bacterial persister cells, crucial for chronic infections, are linked to a novel poly(dC)/RmlB complex in Pseudomonas aeruginosa. Environmental triggers alter this complex, inducing dormancy by reducing cellular energy and impacting antibiotic tolerance.
Area of Science:
- Microbiology
- Bacterial Pathogenesis
- Molecular Biology
Background:
- Bacterial persisters are dormant cells that survive antibiotic treatment, contributing to persistent and recurrent infections.
- Understanding the molecular mechanisms of persister formation is critical for developing new therapeutic strategies against challenging infections.
Purpose of the Study:
- To investigate the role of a novel extracellular poly(dC) and membrane-associated RmlB protein complex in Pseudomonas aeruginosa persistence.
- To elucidate the signaling pathways and cellular changes associated with this complex's role in bacterial dormancy and antibiotic tolerance.
Main Methods:
- Characterization of the poly(dC)/RmlB complex and its environmental state switching in Pseudomonas aeruginosa.
- Analysis of cellular physiological changes, including proton motive force and ATP levels, upon complex state alteration.
- Investigation of the involvement of (p)ppGpp signaling, inorganic polyphosphate, Lon protease, exonuclease VII, and type III secretion system.
Main Results:
- A complex of extracellular poly(dC) and membrane-associated RmlB is identified and linked to Pseudomonas aeruginosa persistence.
- Environmental stimuli induce a switch in the poly(dC)/RmlB complex, leading to decreased proton motive force and ATP levels, promoting cell dormancy.
- This process is regulated by a (p)ppGpp-controlled pathway involving key cellular components and potentially serves as an adaptive response to dTDP-L-rhamnose pathway disruption.
Conclusions:
- The poly(dC)/RmlB complex represents a novel mechanism contributing to bacterial persistence in Pseudomonas aeruginosa.
- Modulation of this complex and its associated signaling pathway offers potential targets for combating chronic and antibiotic-resistant infections.
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