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Anionic self-assembling supramolecular enhancers of antimicrobial efficacy against gram-negative bacteria

Anionic self-assembling supramolecular enhancers of antimicrobial efficacy against gram-negative bacteria
Anionic self-assembling supramolecular enhancers of antimicrobial efficacy against gram-negative bacteria
As a result of the looming antimicrobial resistance crisis, there is an urgent need for novel antimicrobial treatments. This is particularly true for hard-to-treat Gram-negative bacteria, as many antimicrobial agents are unable to cross the cell membrane to gain access to the cell interior, and thus elicit a therapeutic response. Herein, evidence is provided of the use of anionic supramolecular self-associating amphiphiles (SSAs) as antimicrobial efficacy enhancers for commonly used antimicrobial agents, to which there is known resistance, against Gram-negative bacteria. The co-administration of the SSAs with antimicrobials is shown to sensitize traditionally hard to treat Pseudomonas aeruginosa to both rifampicin and novobiocin, from which structure activity relationships can be elucidated. Quantitative fluorescence microscopy is performed, indicating membrane permeabilization to be the likely mode of action of drug efficacy enhancement by the SSAs. These results offer an alternative strategy in antimicrobial adjuvant design, expanding focus beyond cationic peptides and into the realm of anionic small molecules. Finally, the self-assembly of the SSAs in the presence of these antimicrobials is investigated through a combination of quantitative NMR, tensiometry, dynamic light scattering, and zeta potential studies, demonstrating the impact of these agents on SSA self-association events.
2366-3987
Boles, Jessica E.
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Williams, George
26810522-92ef-4b61-a766-582bf15be280
Allen, Nyasha
340bcea8-ba6f-4500-b739-4d41b25bdcca
White, Lisa J.
66137725-b91a-4157-ba97-56607f2dbadf
Hilton, Kira L. F.
cc0687ab-e382-4117-9407-ab836b6f94e3
Popoola, Precious I. A.
58d2cd92-bea0-4b2a-949a-56ea24a50f2a
Mulvihill, Daniel P.
702f83c0-c2e5-48f0-b745-62a7976a248d
Hiscock, Jennifer
c748d645-c150-4751-97bd-54e376f87d01
Boles, Jessica E.
13ce5778-19eb-4276-8328-d865a86f3c2c
Williams, George
26810522-92ef-4b61-a766-582bf15be280
Allen, Nyasha
340bcea8-ba6f-4500-b739-4d41b25bdcca
White, Lisa J.
66137725-b91a-4157-ba97-56607f2dbadf
Hilton, Kira L. F.
cc0687ab-e382-4117-9407-ab836b6f94e3
Popoola, Precious I. A.
58d2cd92-bea0-4b2a-949a-56ea24a50f2a
Mulvihill, Daniel P.
702f83c0-c2e5-48f0-b745-62a7976a248d
Hiscock, Jennifer
c748d645-c150-4751-97bd-54e376f87d01

Boles, Jessica E., Williams, George, Allen, Nyasha, White, Lisa J., Hilton, Kira L. F., Popoola, Precious I. A., Mulvihill, Daniel P. and Hiscock, Jennifer (2022) Anionic self-assembling supramolecular enhancers of antimicrobial efficacy against gram-negative bacteria. Advanced Therapeutics. (doi:10.1002/adtp.202200024).

Record type: Article

Abstract

As a result of the looming antimicrobial resistance crisis, there is an urgent need for novel antimicrobial treatments. This is particularly true for hard-to-treat Gram-negative bacteria, as many antimicrobial agents are unable to cross the cell membrane to gain access to the cell interior, and thus elicit a therapeutic response. Herein, evidence is provided of the use of anionic supramolecular self-associating amphiphiles (SSAs) as antimicrobial efficacy enhancers for commonly used antimicrobial agents, to which there is known resistance, against Gram-negative bacteria. The co-administration of the SSAs with antimicrobials is shown to sensitize traditionally hard to treat Pseudomonas aeruginosa to both rifampicin and novobiocin, from which structure activity relationships can be elucidated. Quantitative fluorescence microscopy is performed, indicating membrane permeabilization to be the likely mode of action of drug efficacy enhancement by the SSAs. These results offer an alternative strategy in antimicrobial adjuvant design, expanding focus beyond cationic peptides and into the realm of anionic small molecules. Finally, the self-assembly of the SSAs in the presence of these antimicrobials is investigated through a combination of quantitative NMR, tensiometry, dynamic light scattering, and zeta potential studies, demonstrating the impact of these agents on SSA self-association events.

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Advanced Therapeutics - 2022 - Boles - Anionic Self‐Assembling Supramolecular Enhancers of Antimicrobial Efficacy against - Version of Record
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e-pub ahead of print date: 20 March 2022

Identifiers

Local EPrints ID: 474154
URI: http://eprints.soton.ac.uk/id/eprint/474154
ISSN: 2366-3987
PURE UUID: 0569e587-8377-4571-8e91-2a1e9598e9f0
ORCID for George Williams: ORCID iD orcid.org/0000-0001-6162-8895

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Date deposited: 14 Feb 2023 17:42
Last modified: 17 Mar 2024 04:17

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Contributors

Author: Jessica E. Boles
Author: George Williams ORCID iD
Author: Nyasha Allen
Author: Lisa J. White
Author: Kira L. F. Hilton
Author: Precious I. A. Popoola
Author: Daniel P. Mulvihill
Author: Jennifer Hiscock

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