Staphylococcus aureus biofilm susceptibility to small and potent β^2,2-amino acid derivatives

Abstract

Small antimicrobial β^2,2-amino acid derivatives (Mw < 500 Da) are reported to display high antibacterial activity against suspended Gram-positive strains combined with low hemolytic activity. In the present study, the anti-biofilm activity of six β^2,2-amino acid derivatives (A1–A6) against Staphylococcus aureus (ATCC 25923) was investigated. The derivatives displayed IC₅₀ values between 5.4 and 42.8 μM for inhibition of biofilm formation, and concentrations between 22.4 and 38.4 μM had substantial effects on preformed biofilms. The lead derivative A2 showed high killing capacity (log R), and it caused distinct ultrastructural changes in the biofilms as shown by electron and atomic force microscopy. The anti-biofilm properties of A2 was preserved under high salinity conditions. Extended screening showed also high activity of A2 against Escherichia coli (XL1 Blue) biofilms. These advantageous features together with high activity against preformed biofilms make β^2,2-amino acid derivatives a promising class of compounds for further development of anti-biofilm agents.

Keywords:

• biofilm
• antimicrobial peptide
• peptidomimetic
• β-amino acid
• electron microscopy
• Escherichia coli

Acknowledgements

The authors thank Randi Olsen and the Electron Microscopy Department, University of Tromsø for the high-pressure cryofixation and sectioning of TEM samples, as well as for scientific advice and assistance. They would also like to express their gratitude to the Research Group in Microbiology, Molecular- and Pharmacoepidemiology, Department of Pharmacy, University of Tromsø for providing access to instruments and laboratories. The scholarship from the University of Tromsø to perform the biofilm experiments at Åbo Akademi University is highly appreciated. The authors also acknowledge the financial support from the Academy of Finland (BIOARMI project, decision 128870; the WOODYFILM project, decision 264064; the ARTFILM project, decision 272266), the Drug Discovery and Chemical Biology (DDCB) network of Biocenter Finland and the Medicinska Understödsföreningen Liv och Hälsa r.f. Funding from The Academy of Finland through the National Center of Excellence programme [grant 118650] is acknowledged.