Worley Travis K, Asal Ayah H, Cooper Lo, Courcelle Charmain T, Courcelle Justin
University of Wisconsin-Madison.
Portland State University.
bioRxiv. 2024 Dec 7:2024.12.03.626702. doi: 10.1101/2024.12.03.626702.
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 transcriptional repressor which also retain the 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 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 expression in the absence of mutation.
交联剂，如补骨脂素和紫外线A辐射，可有效地用作抗菌剂，并用于治疗人类的几种发育异常病症，包括某些癌症。然而，癌细胞和细菌都可能对这些化合物产生抗性，因此了解抗性是如何产生的很重要。最近，分离出了几个突变体，它们通过上调AcrAB-TolC外排泵的组分而对这些化合物产生了高水平的抗性。在这里，我们对这些突变体进行了表征，发现抗性特别需要转录阻遏物的失活突变，这些突变还保留了该编码区域内发现的序列。此外，三种全局调节因子MarA、SoxS或Rob中的任何一种的存在对于结合该序列并激活抗性是必要且充分的。值得注意的是，尽管补骨脂素是外排泵的底物，但这些调节因子对这种应激并非天然响应，因为在没有突变的情况下，补骨脂素、紫外线A或交联诱导均不会上调其表达。
