Biofilm Inhibition via Delivery of Novel Methylthioadenosine Nucleosidase Inhibitors from PVA-Tyramine Hydrogels while Supporting Mesenchymal Stromal Cell Viability

Isha Mutreja, Suzanne L. Warring, Khoon S. Lim, Tara Swadi, Keith Clinch, Jennifer M. Mason, Campbell R. Sheen, Dion R. Thompson, Rodrigo G. Ducati, Stephen T. Chambers, Gary B. Evans, Monica L. Gerth, Antonia G. Miller, Tim B.F. Woodfield

Research output: Contribution to journalArticle

Abstract

The rise of antibiotic resistance, coupled with increased expectations for mobility in later life, is creating a need for biofilm inhibitors and delivery systems that will reduce surgical implant infection. A limitation of some of these existing delivery approaches is toxicity exhibited toward host cells. Here, we report the application of a novel inhibitor of the enzyme, methylthioadenosine nucleosidase (MTAN), a key enzyme in bacterial metabolic pathways, which include S-adenosylmethionine catabolism and purine nucleotide recycling, in combination with a poly(vinyl alcohol)-tyramine-based (PVA-Tyr) hydrogel delivery system. We demonstrate that a lead MTAN inhibitor, selected from a screened library of 34 candidates, (2S)-2-(4-amino-5H-pyrrolo3,2-dpyrimidin-7-ylmethyl)aminoundecan-1-ol (31), showed a minimum biofilm inhibitory concentration of 2.2 ± 0.4 μM against a clinical staphylococcal species isolated from an infected implant. We observed that extracellular DNA, a key constituent of biofilms, is significantly reduced when treated with 10 μM compound 31, along with a decrease in biofilm thickness. Compound 31 was incorporated into a hydrolytically degradable photo-cross-linked PVA-Tyr hydrogel and the release profile was evaluated by HPLC studies. Compound 31 released from the PVA-hydrogel system significantly reduced biofilm formation (77.2 ± 8.4% biofilm inhibition). Finally, compound 31 released from PVA-Tyr showed no negative impact on human bone marrow stromal cell (MSC) viability, proliferation, or morphology. The results demonstrate the potential utility of MTAN inhibitors in treating infections caused by Gram-positive bacteria, and the development of a nontoxic release system that has potential for tunability for time scale of delivery.

Original languageEnglish (US)
JournalACS Biomaterials Science and Engineering
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Tyramine
Hydrogels
Biofilms
Cells
Hydrogel
Alcohols
Enzymes
Purine Nucleotides
S-Adenosylmethionine
Cell proliferation
Enzyme Inhibitors
Antibiotics
Nucleotides
Toxicity
5'-methylthioadenosine phosphorylase
Recycling
Bacteria
Bone
DNA
Lead

Keywords

  • biofilm inhibition
  • hydrogel
  • infection
  • methylthioadenosine nucleosidase
  • PVA-Tyr
  • Staphylococcus

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering

Cite this

Biofilm Inhibition via Delivery of Novel Methylthioadenosine Nucleosidase Inhibitors from PVA-Tyramine Hydrogels while Supporting Mesenchymal Stromal Cell Viability. / Mutreja, Isha; Warring, Suzanne L.; Lim, Khoon S.; Swadi, Tara; Clinch, Keith; Mason, Jennifer M.; Sheen, Campbell R.; Thompson, Dion R.; Ducati, Rodrigo G.; Chambers, Stephen T.; Evans, Gary B.; Gerth, Monica L.; Miller, Antonia G.; Woodfield, Tim B.F.

In: ACS Biomaterials Science and Engineering, 01.01.2019.

Research output: Contribution to journalArticle

Mutreja, Isha ; Warring, Suzanne L. ; Lim, Khoon S. ; Swadi, Tara ; Clinch, Keith ; Mason, Jennifer M. ; Sheen, Campbell R. ; Thompson, Dion R. ; Ducati, Rodrigo G. ; Chambers, Stephen T. ; Evans, Gary B. ; Gerth, Monica L. ; Miller, Antonia G. ; Woodfield, Tim B.F. / Biofilm Inhibition via Delivery of Novel Methylthioadenosine Nucleosidase Inhibitors from PVA-Tyramine Hydrogels while Supporting Mesenchymal Stromal Cell Viability. In: ACS Biomaterials Science and Engineering. 2019.
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abstract = "The rise of antibiotic resistance, coupled with increased expectations for mobility in later life, is creating a need for biofilm inhibitors and delivery systems that will reduce surgical implant infection. A limitation of some of these existing delivery approaches is toxicity exhibited toward host cells. Here, we report the application of a novel inhibitor of the enzyme, methylthioadenosine nucleosidase (MTAN), a key enzyme in bacterial metabolic pathways, which include S-adenosylmethionine catabolism and purine nucleotide recycling, in combination with a poly(vinyl alcohol)-tyramine-based (PVA-Tyr) hydrogel delivery system. We demonstrate that a lead MTAN inhibitor, selected from a screened library of 34 candidates, (2S)-2-(4-amino-5H-pyrrolo3,2-dpyrimidin-7-ylmethyl)aminoundecan-1-ol (31), showed a minimum biofilm inhibitory concentration of 2.2 ± 0.4 μM against a clinical staphylococcal species isolated from an infected implant. We observed that extracellular DNA, a key constituent of biofilms, is significantly reduced when treated with 10 μM compound 31, along with a decrease in biofilm thickness. Compound 31 was incorporated into a hydrolytically degradable photo-cross-linked PVA-Tyr hydrogel and the release profile was evaluated by HPLC studies. Compound 31 released from the PVA-hydrogel system significantly reduced biofilm formation (77.2 ± 8.4{\%} biofilm inhibition). Finally, compound 31 released from PVA-Tyr showed no negative impact on human bone marrow stromal cell (MSC) viability, proliferation, or morphology. The results demonstrate the potential utility of MTAN inhibitors in treating infections caused by Gram-positive bacteria, and the development of a nontoxic release system that has potential for tunability for time scale of delivery.",
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AU - Mason, Jennifer M.

AU - Sheen, Campbell R.

AU - Thompson, Dion R.

AU - Ducati, Rodrigo G.

AU - Chambers, Stephen T.

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