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 journalArticlepeer-review

8 Scopus citations


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)
Pages (from-to)748-758
Number of pages11
JournalACS Biomaterials Science and Engineering
Issue number2
StatePublished - Feb 11 2019

Bibliographical note

Funding Information:
The authors wish to acknowledge the New Zealand Ministry of Business Innovation and Employment for financial support through a Smart Idea Grant (RTVU1504). K.L. is supported by a New Zealand Health Research Council Emerging Researcher First Grant (15/483). T.B.F.W. is a Royal Society of New Zealand Rutherford Discovery Fellowship (RDF-UOO1204). I.M., K.L., and T.B.F.W. are supported by funding from the Medical Technologies Centre of Research Excellence (Med-Tech CoRE). M.L.G., G.E., T.B.F.W., and K.L. are supported by funding from the Maurice Wilkins Centre for Molecular Biodiscovery.

Publisher Copyright:
Copyright © 2018 American Chemical Society.


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


Dive into the research topics of 'Biofilm Inhibition via Delivery of Novel Methylthioadenosine Nucleosidase Inhibitors from PVA-Tyramine Hydrogels while Supporting Mesenchymal Stromal Cell Viability'. Together they form a unique fingerprint.

Cite this