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Enterococcus faecalis alters antibiotic susceptibility in Pseudomonas aeruginosa mixed species biofilms
Open accessPreprint — published as 10.1128/jb.00548-25 · Paper page
Abstract
SUMMARY: Bacterial infections often occur in polymicrobial biofilms where nutrient limitation and interspecies interactions can profoundly shape microbial physiology. Enterococcus faecalis can antagonize Pseudomonas aeruginosa growth under conditions of iron limitation, a known host defense mechanism. We report here that this growth antagonism uncovers surviving P. aeruginosa cells capable of surviving antibiotic challenge, including ampicillin, cefepime, and ciprofloxacin, when grown in iron-restricted biofilms with E. faecalis . Transcriptomic profiling of P. aeruginosa revealed a distinctive response characterized by broad downregulation of biosynthetic, metabolic, and virulence pathways, alongside selective induction of membrane remodeling proteins, transport systems, and biofilm-associated genes. Induction of arnT in P. aeruginosa , required for lipid A modification, correlated with enhanced antibiotic survival to ampicillin, cefepime, and ciprofloxacin. Additionally, the diguanylate cyclase SiaD and efflux transporter MfsC in P. aeruginosa were implicated in decreased antibiotic susceptibility to the same antibiotics above. This transcriptional response was unique to the dual stress of iron deprivation and microbial competition with E. faecalis , illustrating how interspecies interactions can simultaneously inhibit and protect P. aeruginosa , shedding light on potential persistence mechanisms in iron-limited polymicrobial environments. IMPORTANCE: This study addresses antibiotic susceptibility in Pseudomonas aeruginosa , a major opportunistic ESKAPE pathogen, within polymicrobial biofilms and under host-relevant iron-restricted conditions. Polymicrobial biofilm-associated infections are notoriously difficult to treat due to complex interspecies interactions and increased antibiotic resistance. We demonstrate that Enterococcus faecalis not only antagonizes P. aeruginosa growth under iron limitation but also induces a unique transcriptional profile enhancing P. aeruginosa survival during antibiotic challenge. This shift involves broad transcriptional reprogramming in P. aeruginosa , characterized by global metabolic downregulation and activation of envelope remodeling pathways, including the arn operon. These findings reveal how interspecies interactions under iron stress can both suppress and protect bacterial pathogens and underscore the importance of considering community context in treatment strategies for persistent infections.
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Iron in infection and immunity
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Metadata
- Authors
- Anderson, C. M., Mattenberger, Y., Parga, A., Portalier, H., Tan, C. A. Z., Henao, M. E., Viollier, P. H., & Kline, K. A.
- Affiliations
- University of Geneva (CH)
- Nanyang Technological University (SG)
- Corresponding author
- Kline, Kimberly A
- ORCID
- Venue
- Journal of Bacteriology
- Publisher
- openRxiv
- Published
- 2025-11-26
- Volume
- 208
- Issue
- 5
- Pages
- e0054825-e0054825
- ISSN
- 0021-9193 (ISSN-L)
- OpenAlex
- W7158827431
- Cited by
- 2
- References
- 1
- Citations by year
- 2026: 2
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- Locations
- Journal of Bacteriology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DR-NTU (Nanyang Technological University) (submittedVersion)
- Funders
- National Science Foundation
- National Research Foundation
- National University of Singapore
- National Research Foundation Singapore
- Nanyang Technological University
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (219227, 310030)
- Université de Genève
- Société Académique de Genève
- Xunta de Galicia (ED6481B-2023/117)
- Institute of Genetics and Genomics of Geneva
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
- Keywords
- Enterococcus faecalis, Pseudomonas aeruginosa, polymicrobial biofilms, interspecies interactions, iron limitation, antibiotic susceptibility, antibiotic resistance, ARNT, lipid A modification, membrane remodeling, transcriptomic response, persistent infection, ESKAPE pathogens
- MeSH terms
- Anti-Bacterial Agents, Iron, Microbial Sensitivity Tests, Pseudomonas aeruginosa, Enterococcus faecalis, Gene Expression Regulation, Bacterial, Biofilms, Gene Expression Profiling, Drug Resistance, Bacterial, Microbial Interactions
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