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PreprintCited by 14Bacterial Genetics and BiotechnologyEscherichia coli research studiesEnterobacteriaceae and Cronobacter Research

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Conserved Metabolic Regulator ArcA Responds to Oxygen Availability, Iron Limitation, and Cell Envelope Perturbations during Bacteremia

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Brown, Aric N., Anderson, Mark T., Smith, Sara N., Bachman, Michael A., Mobley, Harry L. T.·2023·mBio
DOI 10.1101/2023.04.18.537286PMC PMC10653796

Preprint — published as 10.1128/mbio.01448-23 · Paper page

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Abstract

Bacteremia, a systemic infection associated with severe clinical outcomes, is often caused by Gram-negative facultative anaerobes. ArcAB, a two-component regulatory system that represses aerobic respiration, is a key mediator of metabolic adaptation for such bacteria. Using targeted mutational analysis informed by global genetic screens, we identified the arcA gene as promoting fitness of Klebsiella pneumoniae , Citrobacter freundii , and Serratia marcescens but not Escherichia coli in a murine model of bacteremia. Engineered mutants lacking arcA exhibit a dysregulated response to changes in oxygen availability, iron limitation, and membrane perturbations, all of which bacterial cells experience during infection. The genetic response of the arcA mutants relative to wild-type strains to the cationic antimicrobial peptide polymyxin B demonstrates an expanded role for ArcA as an activator in response to membrane damage in addition to metabolic adaptation. ArcA function is furthermore linked to electron transport chain activity based on its response to uncoupling of proton motive force by carbonyl cyanide- m -chlorophenylhydrazone (CCCP). Differences in lactate and acetate levels as well as lactate dehydrogenase activity between arcA mutant and wild-type cells following CCCP treatment establish an ArcA-mediated shift to fermentation independent of oxygen availability. This study highlights the semi-conserved role of ArcA during bacteremia and consolidates infection phenotypes into a comprehensive model based on respiratory activity. AUTHOR SUMMARY: Infections of the bloodstream are life-threatening and can result in sepsis, an overreaction of the host immune system that ultimately damages the body. Gram-negative bacteria are responsible for causing many cases of bloodstream infections, also referred to as bacteremia. The long-term goal of our work is to understand how these bacteria establish and maintain infection during bacteremia. We have previously identified the transcription factor ArcA, which promotes fermentation in bacteria, as a likely contributor to the growth and survival of bacteria in this environment. Here, we study ArcA in the Gram-negative species Citrobacter freundii , Klebsiella pneumoniae, and Serratia marcescens. Our findings aid in determining how these bacteria sense their environment, utilize nutrients, and generate energy while also countering attacks from the host immune system. This information is critical for developing better models of infection to inform future therapeutic development.

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Metadata

Authors
Brown, A. N., Anderson, M. T., Smith, S. N., Bachman, M. A., & Mobley, H. L. T.
Affiliations
University of Michigan (US)
Corresponding author
Mobley, Harry L. T.
ORCID
Venue
mBio
Publisher
openRxiv
Published
2023-04-18
Volume
14
Issue
5
Pages
e0144823-e0144823
ISSN
2150-7511 (ISSN-L)
DOI
10.1101/2023.04.18.537286
PMC
PMC10653796
OpenAlex
W4386529760
Cited by
14
References
1
Citations by year
2026: 7 · 2025: 3 · 2024: 4
FWCI
2.32
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • mBio (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • American Heart Association (828854)
  • University of Michigan
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (R01AI134731)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Immunology and Microbiology › Microbiology › Escherichia coli research studies
  • Life Sciences › Immunology and Microbiology › Microbiology › Enterobacteriaceae and Cronobacter Research
Keywords
Arca, bacteremia, oxygen availability, iron limitation, polymyxin B, membrane damage, electron transport chain, fermentation, lactate dehydrogenase, Citrobacter freundii, Klebsiella pneumoniae, Serratia marcescens, bacterial metabolism, sepsis
MeSH terms
Gram-Negative Bacteria, Humans, Iron, Klebsiella pneumoniae, Bacteremia, Sepsis

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