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bioRxiv · 10.1101/2024.12.03.626702

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

Worley, T. K.·Asal, A. H.·Cooper, L.·Courcelle, C. T.·Courcelle, J.
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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. HighlightsO_LIPsoralen crosslink resistance requires AcrR inactivation and MarA/SoxS/Rob activation C_LIO_LIPsoralen crosslink resistance is mediated by upregulating the AcrAB-TolC efflux pump C_LIO_LIAcrAB-TolC can utilize psoralen as a substrate but not upregulated by this stress C_LIO_LIAcquiring resistance to DNA interstrand crosslinks requires mutation C_LI

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Worley, T. K., Asal, A. H., Cooper, L., Courcelle, C. T., Courcelle, J.. 2024-12-07. 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. https://doi.org/10.1101/2024.12.03.626702

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