The Complex Development of Psoralen-Interstrand Crosslink Resistance in Escherichia coli requires AcrR inactivation, retention of a marboxsequence, and one 3 of three MarA, SoxS, or Rob Global Regulators

Authors

Travis K. Worley, Portland State University
Ayah H. Asal, Portland State University
Lo Cooper, Portland State University
Charmain T. Courcelle, Portland State University
Justin C. Courcelle, Portland State UniversityFollow

Sponsor

This study was supported by grant MCB1916625 from the National Science Foundation, R21ES034880 from the NIH National Institute of Environmental Health Science, and R16GM14554 from the NIH National Institute of General Medical Sciences.

Published In

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis

Document Type

Pre-Print

Publication Date

2025

Abstract

Crosslinking agents, such as psoralen and UVA radiation, can be effectively used as antimicrobials and for treating several dysplastic conditions in humans, including some cancers. Yet, both cancer cells and bacteria can become resistant to these compounds, making it important to understand how resistance develops. Recently, several mutants were isolated that developed high-levels of resistance to these compounds through upregulation of components of the AcrAB-TolC-efflux pump. Here, we characterized these mutants and found that resistance specifically requires inactivating mutations of the acrR transcriptional repressor which also retain the marbox sequence found within this coding region. In addition, the presence of any one of three global regulators, MarA, SoxS, or Rob, is necessary and sufficient to bind to the marbox sequence and activate resistance. Notably, although psoralen is a substrate for the efflux pump, these regulators are not naturally responsive to this stress as neither psoralen, UVA, nor crosslink induction upregulates acrAB expression in the absence of mutation.

Rights

The copyright holder for this preprint is the author/funder and is made available under a CC-BY-NC-ND 4.0 International license.

Description

This is a pre print version of the article.

The definitive version is published by Elsevier. https://doi.org/10.1016/j.mrfmmm.2025.111898

DOI

10.1016/j.mrfmmm.2025.111898

Publisher

Elsevier BV

Citation Details

Published as: Worley, T. K., Asal, A. H., Cooper, L., Courcelle, C. T., & Courcelle, J. (2025). The Complex development of psoralen-interstrand crosslink resistance in Escherichia coli-requires AcrR inactivation, retention of a marbox sequence, and one of three MarA, SoxS, or Rob global regulators. Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis, 111898.