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Tobramycin-loaded complexes to prevent and disrupt Pseudomonas aeruginosa biofilms

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Abstract

Carbohydrate-based materials are increasingly investigated for a range of applications spanning from healthcare to advanced functional materials. Synthetic glycopolymers are particularly attractive as they possess low toxicity and immunogenicity and can be used as multivalent ligands to target sugar-binding proteins (lectins). Here, we utilised RAFT polymerisation to synthesize two families of novel diblock copolymers consisting of a glycopolymers block containing either mannopyranose or galactopyranose pendant units, which was elongated with sodium 2-acrylamido-2-methyl-1-propanesulfonate (AMPS) to generate a polyanionic block. The latter enabled complexation of cationic aminoglycoside antibiotic tobramycin through electrostatic interactions (loading efficiency in the 0.5–6.3 wt% range, depending on the copolymer). The resulting drug vectors were characterized by dynamic light scattering, zeta-potential, and transmission electron microscopy. Tobramycin-loaded complexes were tested for their ability to prevent clustering or disrupt biofilm of the Pseudomonas aeruginosa Gram-negative bacterium responsible for a large proportion of nosocomial infection, especially in immunocompromised patients. P. aeruginosa possesses two specific tetrameric carbohydrate-binding adhesins, LecA (PA-IL, galactose/N-acetyl-D-galactosamine-binding) and LecB (PA-IIL, fucose/mannose-binding), and the cell-associated and extracellular adhesin CdrA (Psl/mannose-binding) thus ideally suited for targeted drug delivery using sugar-decorated tobramycin-loaded complexes here developed. Both aliphatic and aromatic linkers were utilised to link the sugar pendant units to the polyacrylamide polymer backbone to assess the effect of the nature of such linkers on bactericidal/bacteriostatic properties of the complexes. Results showed that tobramycin-loaded complexes efficiently suppressed (40 to 60% of inhibition) in vitro biofilm formation in PAO1-L P. aeruginosa and that preferential targeting of PAO1-L biofilm can be achieved using mannosylated glycopolymer-b-AMPSm.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding authors.

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Acknowledgements

The authors wish to thank Dr Andrea Pagetta for his assistance with confocal microscopy.

Funding

This research was funded by PRIDJ (grant no. MAST_SID17_01, CUP C93C17002300005); MR, SR and MC are funded by the National Biofilms Innovation Centre (NBIC) which is an Innovation and Knowledge Centre funded by the Biotechnology and Biological Sciences Research Council, InnovateUK and Hartree Centre [Award Number BB/R012415/1].

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Authors and Affiliations

  1. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via F. Marzolo 5, 35131, Padova, Italy

    Delia Boffoli, Federica Bellato, Greta Avancini, Paolo Caliceti, Stefano Salmaso & Francesca Mastrotto

  2. Department of Biology, University of Padova, via U. Bassi 58/B, 35131, Padova, Italy

    Greta Avancini, Francesca Moret & Federica Sandrelli

  3. School of Life Sciences, Nottingham University Biodiscovery Institute, National Biofilms Innovation Centre, University of Nottingham, Nottingham, NG7 2RD, UK

    Shaun Robertson, Francesca Moret & Miguel Cámara

  4. Division of Molecular Therapeutics and Formulation, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK

    Pratik Gurnani, Gokhan Yilmaz & Giuseppe Mantovani

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  1. Delia Boffoli
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  2. Federica Bellato
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  14. Francesca Mastrotto
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DF, PG and GY and FB performed synthesis of monomers and polymers and characterized materials and complexes, DF SR and MR carried out all the biological assays. FB and GA produced fluorescently labelled glycopolymers. FMo, FS and FM performed the biofilm confocal experiments. PC and SS advised on the project. MC supervised all the biological assays. FM and GM equally contributed to the design of the material, the conceptualization of the project, the supervision off all the experimental plan, secured funding and led the writing of the manuscript. All authors have given approval to the final version of the manuscript. Correspondence to Giuseppe Mantovani & Francesca Mastrotto.

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Correspondence to Giuseppe Mantovani or Francesca Mastrotto.

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Boffoli, D., Bellato, F., Avancini, G. et al. Tobramycin-loaded complexes to prevent and disrupt Pseudomonas aeruginosa biofilms. Drug Deliv. and Transl. Res. 12, 1788–1810 (2022). https://doi.org/10.1007/s13346-021-01085-3

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