Transcriptomic analysis of the activity and mechanism of action of a ruthenium(II)-based antimicrobial that induces minimal evolution of pathogen resistance

Varney, A.M., Smitten, K.L., Thomas, J.A. and McLean, S. ORCID: 0000-0001-8551-4307, 2020. Transcriptomic analysis of the activity and mechanism of action of a ruthenium(II)-based antimicrobial that induces minimal evolution of pathogen resistance. ACS Pharmacology & Translational Science. ISSN 2575-9108

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Abstract

Increasing concern over the rising levels of antibiotic resistance amongst pathogenic bacteria has prompted significant research to develop efficacious alternatives to antibiotic treatment. Previously we have reported on the therapeutic activity of a dinuclear ruthenium (II) complex against pathogenic, multidrug resistant bacterial pathogens. Herein, we report that the solubility properties of this lead are comparable to those exhibited by orally available therapeutics, that - in comparison to clinically relevant antibiotics - it induces very slow evolution of resistance in the uropathogenic, therapeutically resistant, E. coli strain EC958 and this resistance was lost when exposure to the compound was temporarily removed. With the aim of further investigating the mechanism of action of this compound, the regulation of nine target genes relating to the membrane, DNA damage and other stress responses provoked by exposure to the compound was also studied. This analysis confirmed that the compound causes a significant transcriptional downregulation of genes involved in membrane transport and the tricarboxylic acid cycle. By contrast, expression of the chaperone protein-coding gene, spy, was significantly increased suggesting a requirement for repair of damaged proteins in the region of the outer membrane. The complex was also found to display activity comparable to that in E. coli in a range of other therapeutically relevant Gram-negative pathogens.

Item Type: Journal article
Alternative Title: A transcriptomic analysis of the activity and mechanism of action of a ruthenium(II)-based antimicrobial that induces minimal evolution of pathogen resistance
Publication Title: ACS Pharmacology & Translational Science
Creators: Varney, A.M., Smitten, K.L., Thomas, J.A. and McLean, S.
Publisher: ACS Publications
Date: 8 December 2020
ISSN: 2575-9108
Identifiers:
NumberType
1389976Other
10.1021/acsptsci.0c00159DOI
Divisions: Schools > School of Science and Technology
Record created by: Linda Sullivan
Date Added: 23 Nov 2020 10:13
Last Modified: 04 Jan 2021 11:38
URI: http://irep.ntu.ac.uk/id/eprint/41676

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