CoChat
Sign Up
PreprintCited by 0Bacterial biofilms and quorum sensingAntimicrobial agents and applicationsAntifungal resistance and susceptibility

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Identification of ferredoxin PA1551 in the bacterial iron uptake pathway and exploration of its antibacterial synergistic as target for biofilm inhibitors against Pseudomonas aeruginosa infection

Open access
Liu, Jun, Ren, Anmin, Miao, Zhiying, Zhou, Tian, Zhang, Chenhui, Chang, Yiqun, Zhao, Siyu, Hu, Xibing, Zhang, Xiaoyi, Jia, Tianyuan, Cai, Zhao, Li, Zhengqiu, Lin, Jing, Yang, Liang, Chen, Weimin·2025·npj Biofilms and Microbiomes
DOI 10.21203/rs.3.rs-6842284/v1PMC PMC12775422

Preprint — published as 10.1038/s41522-025-00871-y · Paper page

Open this paper in CoChat — free accountOpen PDF

Abstract

Addressing antibiotic-resistant bacterial biofilm infections without promoting drug resistance is a pressing challenge. Pseudomonas aeruginosa is well known for causing biofilm-associated drug-resistant infections that often lead to treatment failure. In this study, we identified a previously uncharacterized membrane protein ferredoxin encoded by PA1551 using photoaffinity-based biomimetic probes based on our previous dual-acting antibiofilm compound 2-(heptanamido)methyl 3-hydroxy-1,6-dimethylpyridin-4(1 H )-one ( 10d) . The precision-targeted ferredoxin PA1551 exhibited excellent effectiveness in various model systems, suppressing bacterial biofilm and virulence, and enhancing the antibacterial effects of tobramycin (Tob, by 200-fold) and ciprofloxacin (CIP, by 1000-fold) compared to single-dose antibiotic treatments in a mouse model of Pseudomonas aeruginosa infection. These results indicate that ferredoxin PA1551 can be used as target to design new antibiofilm drugs for the treatment of Pseudomonas aeruginosa infections, particularly challenging bacterial biofilms.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.21203/rs.3.rs-6842284/v1

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 55

  1. Lewis, K. Platforms for antibiotic discovery. Nat. Rev. Drug Discovery 12, 371–387 (2013). · DOI
  2. Brown, E. D. & Wright, G. D. Antibacterial drug discovery in the resistance era. Nature 529, 336–343 (2016). · DOI
  3. Blair, J. M. A. et al. Molecular mechanisms of antibiotic resistance. Nat. Rev. Microbiol. 13, 42–51 (2015). · DOI · Paper page
  4. Rossiter, S. E., Fletcher, M. H. & Wuest, W. M. Natural products as platforms to overcome antibiotic resistance. Chem. Rev. 117, 12415–12474 (2017). · DOI · Paper page
  5. Abouelhassan, Y. et al. Recent progress in natural-product-inspired programs aimed to address antibiotic resistance and tolerance. J. Med. Chem. 62, 7618–7642 (2019). · DOI
  6. Huigens, R. W. et al. Inhibition of Pseudomonas aeruginosa biofilm formation with bromoageliferin analogues. J. Am. Chem. Soc. 129, 6966–6967 (2007). · DOI
  7. Hancock, R. E. W. & Speert, D. P. Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and impact on treatment. Drug Resistance Updates 3, 247–255 (2000). · DOI
  8. Yayan, J., Ghebremedhin, B. & Rasche, K. Antibiotic resistance of Pseudomonas aeruginosa in pneumonia at a single university hospital center in germany over a 10-year period. PLoS One 10, e0139836 (2015). · DOI
  9. Starkey, M. et al. Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity. PLoS Pathog. 10, e1004321 (2014). · DOI
  10. Defoirdt, T. Quorum-sensing systems as targets for antivirulence therapy. Trends Microbiol. 26, 313–328 (2018). · DOI
  11. Nguyen, D. et al. Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria. Science 334, 982–986 (2011). · DOI
  12. Flemming, H. C. & Wingender, J. The biofilm matrix. Nat. Rev. Microbiol. 8, 623–633 (2010). · DOI · Paper page
  13. Wu, Y. K., Cheng, N. C. & Cheng, C. M. Biofilms in chronic wounds: pathogenesis and diagnosis. Trends Biotechnol. 37, 505–517 (2019). · DOI
  14. James, G. A. et al. Biofilms in chronic wounds. Wound Repair Regen. 16, 37–44 (2008). · DOI · Paper page
  15. Kolpen, M. et al. Bacterial biofilms predominate in both acute and chronic human lung infections. Thorax 77, 1015–1022 (2022). · DOI
  16. Versey, Z. et al. Biofilm-innate immune interface: contribution to chronic wound formation. Front. Immunol. 12, 648554 (2021). · DOI
  17. Sauer, K. et al. The biofilm life cycle: expanding the conceptual model of biofilm formation. Nat. Rev. Microbiol. 20, 608–620 (2022). · DOI
  18. Martin, P. & Leibovich, S. J. Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol. 15, 599–607 (2005). · DOI · Paper page
  19. Percival, S. L., McCarty, S. M. & Lipsky, B. Biofilms and wounds: an overview of the evidence. Adv. Wound Care 4, 373–381 (2015). · DOI
  20. Liu, J. et al. Novel 2-substituted 3-hydroxy-1,6-dimethylpyridin-4(1H)-ones as dual-acting biofilm inhibitors of Pseudomonas aeruginosa. J. Med. Chem. 63, 10921–10945 (2020). · DOI
  21. Liu, J. et al. New pqs quorum sensing system inhibitor as an antibacterial synergist against multidrug-resistant Pseudomonas aeruginosa. J. Med. Chem. 65, 688–709 (2022). · DOI
  22. Ziegler, S., Pries, V., Hedberg, C. & Waldmann, H. Target identification for small bioactive molecules: finding the needle in the haystack. Angew. Chem., Int. Ed. Engl. 52, 2744–2792 (2013). · DOI
  23. Kleiner, P. et al. A whole proteome inventory of background photocrosslinker binding. Angew. Chem., Int. Ed. 56, 1396–1401 (2017). · DOI
  24. Pan, S. et al. Target identification of natural products and bioactive compounds using affinity-based probes. Nat. Prod. Rep. 33, 612–620 (2016). · DOI
  25. Li, Z. et al. Design and synthesis of minimalist terminal alkyne-containing diazirine photo-crosslinkers and their incorporation into kinase inhibitors for cell- and tissue-based proteome profiling. Angew. Chem., Int. Ed. 52, 8551–8556 (2013). · DOI
  26. Schütz, C. et al. A new pqsR inverse agonist potentiates tobramycin efficacy to eradicate Pseudomonas aeruginosa biofilms. Adv. Sci. 8, e2004369 (2021). · DOI
  27. West, K. H. J. et al. Sustained release of a synthetic autoinducing peptide mimetic blocks bacterial communication and virulence in vivo. Angew. Chem., Int. Ed. Engl. 61, e202201798 (2022). · DOI
  28. Thorn, C. R. et al. Liquid crystal nanoparticles enhance tobramycin efficacy in a murine model of Pseudomonas aeruginosa biofilm wound infection. ACS Infect. Dis. 8, 841–854 (2022). · DOI
  29. Tian, S. et al. Self-targeting, zwitterionic micellar dispersants enhance antibiotic killing of infectious biofilms-An intravital imaging study in mice. Sci. Adv. 6, eabb1112 (2020). · DOI
  30. Hatanaka, Y. & Sadakane, Y. Photoaffinity labeling in drug discovery and developments: chemical gateway for entering proteomic frontier. Curr. Top. Med. Chem. 2, 271–288 (2002). · DOI
  31. Halloran, M. W. & Lumb, J. P. Recent applications of diazirines in chemical proteomics. Chemistry (Weinheim an der Bergstrasse, Germany) 25, 4885–4898 (2019).
  32. Shi, H., Zhang, C. J., Chen, G. Y. & Yao, S. Q. Cell-based proteome profiling of potential dasatinib targets by use of affinity-based probes. J. Am. Chem. Soc. 134, 3001–3014 (2012). · DOI
  33. DeLange, P. A., Collins, T. L., Pierce, G. E. & Robinson, J. B. PilJ localizes to cell poles and is required for type IV pilus extension in Pseudomonas aeruginosa. Curr. Microbiol. 55, 389–395 (2007). · DOI
  34. Hazan, R. et al. Auto poisoning of the respiratory chain by a quorum-sensing-regulated molecule favors biofilm formation and antibiotic tolerance. Curr. Biol. 26, 195–206 (2016). · DOI
  35. Xie, H. et al. Biochemical and biophysical characterization of the two isoforms of cbb3-type cytochrome c oxidase from Pseudomonas stutzeri. J. Bacteriol. 196, 472–482 (2014). · DOI
  36. Fulton, R. L., Irons, J. & Downs, D. M. The cysteine desulfurase Iscs Is a significant target of 2-aminoacrylate damage in Pseudomonas aeruginosa. mBio 13, e0107122 (2022). · DOI
  37. Douafer, H., Andrieu, V., Phanstiel, O. t. & Brunel, J. M. Antibiotic adjuvants: make antibiotics great again! J. Med. Chem. 62, 8665–8681 (2019). · DOI
  38. Otaka, E. & Ooi, T. Examination of protein sequence homologies: IV. Twenty-seven bacterial ferredoxins. J. Mol. Evol. 26, 257–267 (1987). · DOI
  39. Duée, E. D. et al. Refined crystal structure of the 2[4Fe-4S] ferredoxin from clostridium acidurici at 1.84 A resolution. J. Mol. Biol. 243, 683–695 (1994). · DOI
  40. Stover, C. K. et al. Complete genome sequence of Pseudomonas aeruginosa PAO1, an opportunistic pathogen. Nature 406, 959–964 (2000). · DOI
  41. He, X. et al. A fast and high-quality charge model for the next generation general AMBER force field. J. Chem. Phys. 153, 114502 (2020). · DOI
  42. Lomize, M. A. et al. OPM database and PPM web server: resources for positioning of proteins in membranes. Nucleic Acids Res. 40, D370-376 (2012). · DOI
  43. Chen, S. M. The electrocatalytic reactions of cysteine and cystine by water-soluble iron porphyrin, manganese porphyrin and iron(II) phenanthrolines. Electrochim. Acta 42, 1663–1673 (1997). · DOI
  44. Ganne, G. et al. Iron release from the siderophore pyoverdine in Pseudomonas aeruginosa involves three new actors: FpvC, FpvG, and FpvH. ACS Chem. Biol. 12, 1056–1065 (2017). · DOI
  45. Stookey, L. L. Ferrozine—a new spectrophotometric reagent for iron. Anal. Chem. 42, 779–781 (1970). · DOI
  46. Qu, D. et al. A new coumarin compound DCH combats methicillin-resistant Staphylococcus aureus biofilm by targeting arginine repressor. Sci. Adv. 6, eaay9597 (2020). · DOI
  47. Zhao, X. L. et al. Glutamine promotes antibiotic uptake to kill multidrug-resistant uropathogenic bacteria. Sci. Transl. Med. 13, eabj0716 (2021). · DOI
  48. Bonneau, A., Roche, B. & Schalk, I. J. Iron acquisition in Pseudomonas aeruginosa by the siderophore pyoverdine: an intricate interacting network including periplasmic and membrane proteins. Sci. Rep. 10, 120 (2020). · DOI
  49. Imperi, F., Tiburzi, F. & Visca, P. Molecular basis of pyoverdine siderophore recycling in Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. U. S. A. 106, 20440–20445 (2009).
  50. Fong, J. et al. Disulfide bond-containing ajoene analogues as novel quorum sensing inhibitors of Pseudomonas aeruginosa. J. Med. Chem. 60, 215–227 (2017). · DOI
  51. Rybtke, M. T. et al. Fluorescence-based reporter for gauging cyclic di-GMP levels in Pseudomonas aeruginosa. Appl. Environ. Microbiol. 78, 5060–5069 (2012). · DOI
  52. Wang, T. et al. Type VI secretion system transports Zn2+ to combat multiple stresses and host immunity. PLoS Pathog. 11, e1005020 (2015). · DOI · Paper page
  53. Schrödinger release 2023-1: protein preparation wizard; epik, Schrödinger, LLC, New York, NY, 2023.
  54. Schrödinger release 2023-1: desmond molecular dynamics system, D. E. Shaw Research, New York, NY, 2023.
  55. Schrödinger release 2023-1: glide, Schrödinger, LLC, New York, NY, 2023.

Metadata

Authors
Liu, J., Ren, A., Miao, Z., Zhou, T., Zhang, C., Chang, Y., Zhao, S., Hu, X., Zhang, X., Jia, T., Cai, Z., Li, Z., Lin, J., Yang, L., & Chen, W.
Affiliations
  • Jinan University (CN)
  • Southern University of Science and Technology (CN)
  • The University of Sydney (AU)
  • Jinan University
Corresponding author
  • Liu, Jun
  • Yang, Liang
ORCID
Venue
npj Biofilms and Microbiomes
Publisher
Springer Science and Business Media LLC
Published
2025-06-18
Volume
12
Issue
1
Pages
5-5
ISSN
2055-5008 (ISSN-L)
DOI
10.21203/rs.3.rs-6842284/v1
PMC
PMC12775422
OpenAlex
W4417045231
Cited by
0
References
1
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • npj Biofilms and Microbiomes (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (82173651, 82473788)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
  • Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Antimicrobial agents and applications
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Keywords
Pseudomonas aeruginosa, bacterial biofilms, antibiotic synergy, photoaffinity labeling, membrane proteins, antibiotic resistance, tobramycin, ciprofloxacin, virulence suppression, wound infection
MeSH terms
Animals, Anti-Bacterial Agents, Bacterial Proteins, Ciprofloxacin, Disease Models, Animal, Drug Synergism, Ferredoxins, Microbial Sensitivity Tests, Pseudomonas aeruginosa, Pseudomonas Infections, Tobramycin, Wound Infection, Biofilms, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review