Surfaces modified with small molecules that interfere with nucleotide signaling reduce Staphylococcus epidermidis biofilm and increase the efficacy of ciprofloxacin

Staphylococcus epidermidis are common bacteria associated with biofilm related infections on implanted medical devices. Antibiotics are often used in combating such infections, but they may lose their efficacy in the presence of biofilms. Bacterial intracellular nucleotide second messenger signaling plays an important role in biofilm formation, and interference with the nucleotide signaling pathways provides a possible way to control biofilm formation and to increase biofilm susceptibility to antibiotic therapy. This study synthesized small molecule derivates of 4-arylazo-3,5-diamino-1 H-pyrazole (named as SP02 and SP03) and found these molecules inhibited S. epidermidis biofilm formation and induced biofilm dispersal. Analysis of bacterial nucleotide signaling molecules showed that both SP02 and SP03 significantly reduced cyclic dimeric adenosine monophosphate (c-di-AMP) levels in S. epidermidis at doses as low as 25 µM while having significant effects on multiple nucleotides signaling including cyclic dimeric guanosine monophosphate (c-di-GMP), c-di-AMP, and cyclic adenosine monophosphate (cAMP) at high doses (100 µM or greater). We then tethered these small molecules to polyurethane (PU) biomaterial surfaces and investigated biofilm formation on the modified surfaces. Results showed that the modified surfaces significantly inhibited biofilm formation during 24 h and 7-day incubations. The antibiotic ciprofloxacin was used to treat these biofilms and the efficacy of the antibiotic (2 µg/mL) was found to increase from 94.8% on unmodified PU surfaces to > 99.9% on both SP02 and SP03 modified surfaces (>3 log units). Results demonstrated the feasibility of tethering small molecules that interfere with nucleotide signaling onto polymeric biomaterial surfaces and in a way that interrupts biofilm formation and increases antibiotic efficacy for S. epidermidis infections.

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Work Title Surfaces modified with small molecules that interfere with nucleotide signaling reduce Staphylococcus epidermidis biofilm and increase the efficacy of ciprofloxacin
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Open Access
Creators
  1. Li-Chong Xu
  2. Alyssa Ochetto
  3. Chen Chen
  4. Dongxiao Sun
  5. Harry R. Allcock
  6. Christopher A. Siedlecki
Keyword
  1. Nucleotide
  2. C-di-AMP
  3. C-di-GMP
  4. Biofilm
  5. Small molecule
  6. Efficacy of antibiotics
License In Copyright (Rights Reserved)
Work Type Article
Publisher
  1. Colloids and Surfaces B: Biointerfaces
Publication Date May 15, 2023
Publisher Identifier (DOI)
  1. https://doi.org/10.1016/j.colsurfb.2023.113345
Deposited February 19, 2024

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Version 1
published

  • Created
  • Added Colloids_Surface_B__Xu.pdf
  • Added Creator Li Chong Xu
  • Added Creator Alyssa Ochetto
  • Added Creator Chen Chen
  • Added Creator Dongxiao Sun
  • Added Creator Harry R. Allcock
  • Added Creator Christopher A. Siedlecki
  • Published
  • Updated Keyword, Description, Publication Date Show Changes
    Keyword
    • Nucleotide, C-di-AMP, C-di-GMP, Biofilm, Small molecule, Efficacy of antibiotics
    Description
    • <p>Staphylococcus epidermidis are common bacteria associated with biofilm related infections on implanted medical devices. Antibiotics are often used in combating such infections, but they may lose their efficacy in the presence of biofilms. Bacterial intracellular nucleotide second messenger signaling plays an important role in biofilm formation, and interference with the nucleotide signaling pathways provides a possible way to control biofilm formation and to increase biofilm susceptibility to antibiotic therapy. This study synthesized small molecule derivates of 4-arylazo-3,5-diamino-1 H-pyrazole (named as SP02 and SP03) and found these molecules inhibited S. epidermidis biofilm formation and induced biofilm dispersal. Analysis of bacterial nucleotide signaling molecules showed that both SP02 and SP03 significantly reduced cyclic dimeric adenosine monophosphate (c-di-AMP) levels in S. epidermidis at doses as low as 25 µM while having significant effects on multiple nucleotides signaling including cyclic dimeric guanosine monophosphate (c-di-GMP), c-di-AMP, and cyclic adenosine monophosphate (cAMP) at high doses (100 µM or greater). We then tethered these small molecules to polyurethane (PU) biomaterial surfaces and investigated biofilm formation on the modified surfaces. Results showed that the modified surfaces significantly inhibited biofilm formation during 24 h and 7-day incubations. The antibiotic ciprofloxacin was used to treat these biofilms and the efficacy of the antibiotic (2 µg/mL) was found to increase from 94.8% on unmodified PU surfaces to &gt; 99.9% on both SP02 and SP03 modified surfaces (&gt;3 log units). Results demonstrated the feasibility of tethering small molecules that interfere with nucleotide signaling onto polymeric biomaterial surfaces and in a way that interrupts biofilm formation and increases antibiotic efficacy for S. epidermidis infections.</p>
    • <p>_Staphylococcus epidermidis_ are common bacteria associated with biofilm related infections on implanted medical devices. Antibiotics are often used in combating such infections, but they may lose their efficacy in the presence of biofilms. Bacterial intracellular nucleotide second messenger signaling plays an important role in biofilm formation, and interference with the nucleotide signaling pathways provides a possible way to control biofilm formation and to increase biofilm susceptibility to antibiotic therapy. This study synthesized small molecule derivates of 4-arylazo-3,5-diamino-1 H-pyrazole (named as SP02 and SP03) and found these molecules inhibited _S. epidermidis_ biofilm formation and induced biofilm dispersal. Analysis of bacterial nucleotide signaling molecules showed that both SP02 and SP03 significantly reduced cyclic dimeric adenosine monophosphate (c-di-AMP) levels in _S. epidermidis_ at doses as low as 25 µM while having significant effects on multiple nucleotides signaling including cyclic dimeric guanosine monophosphate (c-di-GMP), c-di-AMP, and cyclic adenosine monophosphate (cAMP) at high doses (100 µM or greater). We then tethered these small molecules to polyurethane (PU) biomaterial surfaces and investigated biofilm formation on the modified surfaces. Results showed that the modified surfaces significantly inhibited biofilm formation during 24 h and 7-day incubations. The antibiotic ciprofloxacin was used to treat these biofilms and the efficacy of the antibiotic (2 µg/mL) was found to increase from 94.8% on unmodified PU surfaces to &gt; 99.9% on both SP02 and SP03 modified surfaces (&gt;3 log units). Results demonstrated the feasibility of tethering small molecules that interfere with nucleotide signaling onto polymeric biomaterial surfaces and in a way that interrupts biofilm formation and increases antibiotic efficacy for _S. epidermidis_ infections.</p>
    Publication Date
    • 2023-07-01
    • 2023-05-15
  • Renamed Creator Li-Chong Xu Show Changes
    • Li Chong Xu
    • Li-Chong Xu
  • Updated

Version 2
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  • Deleted Colloids_Surface_B__Xu.pdf
  • Added Colloid Surface B_Revised _clean version 03-30-2023.docx
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