CyuR is a Dual Regulator for L-Cysteine Dependent Antimicrobial Resistance inEscherichia coli

Abstract

ABSTRACTHydrogen sulfide (H2S), mainly produced from L-cysteine (Cys), renders bacteria highly resistant to oxidative stress. This mitigation of oxidative stress was suggested to be an important survival mechanism to achieve antimicrobial resistance (AMR) in many pathogenic bacteria. CyuR (known as DecR or YbaO) is a recently characterized Cys-dependent transcription regulator, responsible for the activation of thecyuAPoperon and generation of hydrogen sulfide from Cys. Despite its potential importance, the regulatory network of CyuR remains poorly understood. In this study, we investigated the roles of the CyuR regulon in a Cys-dependent AMR mechanism inE. colistrains. We found: 1) Cys metabolism has a significant role in AMR and its effect is conserved in manyE. colistrains, including clinical isolates; 2) CyuR negatively controls the expression ofmdlABencoding a transporter that exports antibiotics such as cefazolin and vancomycin; 3) CyuR binds to a DNA sequence motif ‘GAAwAAATTGTxGxxATTTsyCC’ in the absence of Cys, confirmed by anin vitrobinding assay; and 4) CyuR may regulate 25 additional genes as suggested byin silicomotif scanning and transcriptome sequencing. Collectively, our findings expanded the understanding of the biological roles of CyuR relevant to antibiotic resistance associated with Cys.