Dimeric peptoids as antibacterial agents.

Bahatheg, G; Kuppusamy, R; Yasir, M; Bridge, S; Mishra, SK; Cranfield, CG; StC Black, D; Willcox, M; Kumar, N

Dimeric peptoids as antibacterial agents.

Bahatheg, G Kuppusamy, R Yasir, M Bridge, S Mishra, SK Cranfield, CG StC Black, D Willcox, M Kumar, N

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Publisher:: ACADEMIC PRESS INC ELSEVIER SCIENCE
Publication Type:: Journal Article
Citation:: Bioorg Chem, 2024, 147, pp. 107334
Issue Date:: 2024-06

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Field	Value	Language
dc.contributor.author	Bahatheg, G
dc.contributor.author	Kuppusamy, R
dc.contributor.author	Yasir, M
dc.contributor.author	Bridge, S
dc.contributor.author	Mishra, SK
dc.contributor.author	Cranfield, CG
dc.contributor.author	StC Black, D
dc.contributor.author	Willcox, M
dc.contributor.author	Kumar, N
dc.date.accessioned	2024-12-20T03:58:31Z
dc.date.available	2024-04-02
dc.date.available	2024-12-20T03:58:31Z
dc.date.issued	2024-06
dc.identifier.citation	Bioorg Chem, 2024, 147, pp. 107334
dc.identifier.issn	0045-2068
dc.identifier.issn	1090-2120
dc.identifier.uri	http://hdl.handle.net/10453/182728
dc.description.abstract	Building upon our previous study on peptoid-based antibacterials which showed good activity against Gram-positive bacteria only, herein we report the synthesis of 34 dimeric peptoid compounds and the investigation of their activity against Gram-positive and Gram-negative pathogens. The newly designed peptoids feature a di-hydrophobic moiety incorporating phenyl, bromo-phenyl, and naphthyl groups, combined with variable lengths of cationic units such as amino and guanidine groups. The study also underscores the pivotal interplay between hydrophobicity and cationicity in optimizing efficacy against specific bacteria. The bromophenyl dimeric guanidinium peptoid compound 10j showed excellent activity against S. aureus 38 and E. coli K12 with MIC of 0.8 μg mL-1 and 6.2 μg mL-1, respectively. Further investigation into the mechanism of action revealed that the antibacterial effect might be attributed to the disruption of bacterial cell membranes, as suggested by tethered bilayer lipid membranes (tBLMs) and cytoplasmic membrane permeability studies. Notably, these promising antibacterial agents exhibited negligible toxicity against mammalian red blood cells. Additionally, the study explored the potential of 12 active compounds to disrupt established biofilms of S. aureus 38. The most effective biofilm disruptors were ethyl and octyl-naphthyl guanidinium peptoids (10c and 10 k). These compounds 10c and 10 k disrupted the established biofilms of S. aureus 38 with 51 % at 4x MIC (MIC = 17.6 μg mL-1 and 11.2 μg mL-1) and 56 %-58 % at 8x MIC (MIC = 35.2 μg mL-1 and 22.4 μg mL-1) respectively. Overall, this research contributes insights into the design principles of cationic dimeric peptoids and their antibacterial activity, with implications for the development of new antibacterial compounds.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	ACADEMIC PRESS INC ELSEVIER SCIENCE
dc.relation.ispartof	Bioorg Chem
dc.relation.isbasedon	10.1016/j.bioorg.2024.107334
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry
dc.subject.classification	Organic Chemistry
dc.subject.classification	3404 Medicinal and biomolecular chemistry
dc.subject.classification	3405 Organic chemistry
dc.subject.mesh	Anti-Bacterial Agents
dc.subject.mesh	Peptoids
dc.subject.mesh	Microbial Sensitivity Tests
dc.subject.mesh	Biofilms
dc.subject.mesh	Staphylococcus aureus
dc.subject.mesh	Structure-Activity Relationship
dc.subject.mesh	Molecular Structure
dc.subject.mesh	Dose-Response Relationship, Drug
dc.subject.mesh	Dimerization
dc.subject.mesh	Escherichia coli
dc.subject.mesh	Humans
dc.subject.mesh	Erythrocytes
dc.subject.mesh	Erythrocytes
dc.subject.mesh	Humans
dc.subject.mesh	Biofilms
dc.subject.mesh	Escherichia coli
dc.subject.mesh	Staphylococcus aureus
dc.subject.mesh	Peptoids
dc.subject.mesh	Anti-Bacterial Agents
dc.subject.mesh	Microbial Sensitivity Tests
dc.subject.mesh	Molecular Structure
dc.subject.mesh	Structure-Activity Relationship
dc.subject.mesh	Dimerization
dc.subject.mesh	Dose-Response Relationship, Drug
dc.subject.mesh	Anti-Bacterial Agents
dc.subject.mesh	Peptoids
dc.subject.mesh	Microbial Sensitivity Tests
dc.subject.mesh	Biofilms
dc.subject.mesh	Staphylococcus aureus
dc.subject.mesh	Structure-Activity Relationship
dc.subject.mesh	Molecular Structure
dc.subject.mesh	Dose-Response Relationship, Drug
dc.subject.mesh	Dimerization
dc.subject.mesh	Escherichia coli
dc.subject.mesh	Humans
dc.subject.mesh	Erythrocytes
dc.title	Dimeric peptoids as antibacterial agents.
dc.type	Journal Article
utslib.citation.volume	147
utslib.location.activity	United States
utslib.for	0304 Medicinal and Biomolecular Chemistry
utslib.for	0305 Organic Chemistry
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/Centre for Health Technologies (CHT)
pubs.organisational-group	University of Technology Sydney/UTS Groups/Institute of Biomedical Materials and Devices (IBMD)
pubs.organisational-group	University of Technology Sydney/UTS Groups/Institute of Biomedical Materials and Devices (IBMD)/Institute of Biomedical Materials and Devices (IBMD) Associate Members
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2024-12-20T03:58:29Z
pubs.publication-status	Published
pubs.volume	147

Abstract:

Building upon our previous study on peptoid-based antibacterials which showed good activity against Gram-positive bacteria only, herein we report the synthesis of 34 dimeric peptoid compounds and the investigation of their activity against Gram-positive and Gram-negative pathogens. The newly designed peptoids feature a di-hydrophobic moiety incorporating phenyl, bromo-phenyl, and naphthyl groups, combined with variable lengths of cationic units such as amino and guanidine groups. The study also underscores the pivotal interplay between hydrophobicity and cationicity in optimizing efficacy against specific bacteria. The bromophenyl dimeric guanidinium peptoid compound 10j showed excellent activity against S. aureus 38 and E. coli K12 with MIC of 0.8 μg mL-1 and 6.2 μg mL-1, respectively. Further investigation into the mechanism of action revealed that the antibacterial effect might be attributed to the disruption of bacterial cell membranes, as suggested by tethered bilayer lipid membranes (tBLMs) and cytoplasmic membrane permeability studies. Notably, these promising antibacterial agents exhibited negligible toxicity against mammalian red blood cells. Additionally, the study explored the potential of 12 active compounds to disrupt established biofilms of S. aureus 38. The most effective biofilm disruptors were ethyl and octyl-naphthyl guanidinium peptoids (10c and 10 k). These compounds 10c and 10 k disrupted the established biofilms of S. aureus 38 with 51 % at 4x MIC (MIC = 17.6 μg mL-1 and 11.2 μg mL-1) and 56 %-58 % at 8x MIC (MIC = 35.2 μg mL-1 and 22.4 μg mL-1) respectively. Overall, this research contributes insights into the design principles of cationic dimeric peptoids and their antibacterial activity, with implications for the development of new antibacterial compounds.

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http://hdl.handle.net/10453/182728