TY - JOUR
T1 - Inhibition of Staphylococcus aureus biofilm-forming functional amyloid by molecular tweezers
AU - Malishev, Ravit
AU - Salinas, Nir
AU - Gibson, James
AU - Eden, Angela Bailey
AU - Mieres-Perez, Joel
AU - Ruiz-Blanco, Yasser B.
AU - Malka, Orit
AU - Kolusheva, Sofiya
AU - Klärner, Frank Gerrit
AU - Schrader, Thomas
AU - Sanchez-Garcia, Elsa
AU - Wang, Chunyu
AU - Landau, Meytal
AU - Bitan, Gal
AU - Jelinek, Raz
N1 - Funding Information:
The authors are grateful to Nitzan Shauloff (Ben Gurion University) for help with SEM imaging and graphical abstract design. We acknowledge Prof. Elena Voronov (Ben Gurion University) for her assistance with the mouse blood and mouse serum samples in the project. E.S.-G. was supported by the collaborative research center CRC 1093 “Supramolecular Chemistry on Proteins” and by Germany's Excellence Strategy – EXC 2033–390677874 – RESOLV, both funded by the German Research Foundation (DFG). E.S.-G. also acknowledges the support of the Boehringer Ingelheim Foundation (Plus-3 Program) and computing time at the supercomputer Magnitude. G.B. acknowledges support by NIH/NIA grants R01AG050721 and RF1AG054000. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. A patent related to the molecular tweezers has been awarded: G. Bitan, A. Shanmugam, A. Lomakin, T. Schrader, F.G. Klärner, P. Talbierski, J. Polkowska, F. Bastowski, S. Sinha, and S. Frautschy (2009) Molecular Tweezers for the Treatment of Amyloid-Related Diseases. International Patent No. PCT/US2010/026419, USA Patent No. 8,791,092, European Patent No. EP2403859 A2.
Funding Information:
The authors are grateful to Nitzan Shauloff (Ben Gurion University) for help with SEM imaging and graphical abstract design. We acknowledge Prof. Elena Voronov (Ben Gurion University) for her assistance with the mouse blood and mouse serum samples in the project. E.S.-G. was supported by the collaborative research center CRC 1093 “Supramolecular Chemistry on Proteins” and by Germany's Excellence Strategy – EXC 2033 – 390677874 – RESOLV, both funded by the German Research Foundation ( DFG ). E.S.-G. also acknowledges the support of the Boehringer Ingelheim Foundation (Plus-3 Program) and computing time at the supercomputer Magnitude. G.B. acknowledges support by NIH / NIA grants R01AG050721 and RF1AG054000 .
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/9/16
Y1 - 2021/9/16
N2 - Biofilms are rigid and largely impenetrable three-dimensional matrices constituting virulence determinants of various pathogenic bacteria. Here, we demonstrate that molecular tweezers, unique supramolecular artificial receptors, modulate biofilm formation of Staphylococcus aureus. In particular, the tweezers affect the structural and assembly properties of phenol-soluble modulin α1 (PSMα1), a biofilm-scaffolding functional amyloid peptide secreted by S. aureus. The data reveal that CLR01, a diphosphate tweezer, exhibits significant S. aureus biofilm inhibition and disrupts PSMα1 self-assembly and fibrillation, likely through inclusion of lysine side chains of the peptide. In comparison, different peptide binding occurs in the case of CLR05, a tweezer containing methylenecarboxylate units, which exhibits lower affinity for the lysine residues yet disrupts S. aureus biofilm more strongly than CLR01. Our study points to a possible role for molecular tweezers as potent biofilm inhibitors and antibacterial agents, particularly against untreatable biofilm-forming and PSM-producing bacteria, such as methicillin-resistant S. aureus.
AB - Biofilms are rigid and largely impenetrable three-dimensional matrices constituting virulence determinants of various pathogenic bacteria. Here, we demonstrate that molecular tweezers, unique supramolecular artificial receptors, modulate biofilm formation of Staphylococcus aureus. In particular, the tweezers affect the structural and assembly properties of phenol-soluble modulin α1 (PSMα1), a biofilm-scaffolding functional amyloid peptide secreted by S. aureus. The data reveal that CLR01, a diphosphate tweezer, exhibits significant S. aureus biofilm inhibition and disrupts PSMα1 self-assembly and fibrillation, likely through inclusion of lysine side chains of the peptide. In comparison, different peptide binding occurs in the case of CLR05, a tweezer containing methylenecarboxylate units, which exhibits lower affinity for the lysine residues yet disrupts S. aureus biofilm more strongly than CLR01. Our study points to a possible role for molecular tweezers as potent biofilm inhibitors and antibacterial agents, particularly against untreatable biofilm-forming and PSM-producing bacteria, such as methicillin-resistant S. aureus.
KW - MRSA
KW - PSMa1
KW - Staphylococcus aureus
KW - amyloid peptides
KW - antibacterial
KW - biofilm
KW - functional amyloid
KW - molecular tweezer
KW - phenol-soluble modulins
UR - http://www.scopus.com/inward/record.url?scp=85105008125&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2021.03.013
DO - 10.1016/j.chembiol.2021.03.013
M3 - Article
C2 - 33852903
AN - SCOPUS:85105008125
SN - 2451-9448
VL - 28
SP - 1310-1320.e5
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 9
ER -