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CarR, a MarR-family regulator from Corynebacterium glutamicum, modulated antibiotic and aromatic compound resistance
Meiru Si1, Can Chen2, Zengfan Wei1
1College of Life Sciences, Qufu Normal University, Qufu, Shandong 273165, China.
Abstract:
MarR (multiple antibiotic resistance regulator) proteins are a family of transcriptional regulators that is prevalent in Corynebacterium glutamicum. Understanding the physiological and biochemical function of MarR homologs in C. glutamicum has focused on cysteine oxidation-based redox-sensing and substrate metabolism-involving regulators. In this study, we characterized the stress-related ligand-binding functions of the C. glutamicum MarR-type regulator CarR (C. glutamicum antibiotic-responding regulator). We demonstrate that CarR negatively regulates the expression of the carR (ncgl2886)-uspA (ncgl2887) operon and the adjacent, oppositely oriented gene ncgl2885, encoding the hypothetical deacylase DecE. We also show that CarR directly activates transcription of the ncgl2882-ncgl2884 operon, encoding the peptidoglycan synthesis operon (PSO) located upstream of carR in the opposite orientation. The addition of stress-associated ligands such as penicillin and streptomycin induced carR, uspA, decE, and PSO expression in vivo, as well as attenuated binding of CarR to operator DNA in vitro. Importantly, stress response-induced up-regulation of carR, uspA, and PSO gene expression correlated with cell resistance to β-lactam antibiotics and aromatic compounds. Six highly conserved residues in CarR were found to strongly influence its ligand binding and transcriptional regulatory properties. Collectively, the results indicate that the ligand binding of CarR induces its dissociation from the carR-uspA promoter to derepress carR and uspA transcription. Ligand-free CarR also activates PSO expression, which in turn contributes to C. glutamicum stress resistance. The outcomes indicate that the stress response mechanism of CarR in C. glutamicum occurs via ligand-induced conformational changes to the protein, not via cysteine oxidation-based thiol modifications.
Insights
The C. glutamicum CarR regulator controls antibiotic resistance by binding stress ligands, which alters its DNA binding and gene expression. This mechanism enhances cell survival against antibiotics and aromatic compounds.
Area of Science:
- Microbiology
- Molecular Biology
- Biochemistry
Background:
- MarR (multiple antibiotic resistance regulator) proteins are transcriptional regulators found in Corynebacterium glutamicum.
- Previous studies focused on redox-sensing and metabolism-related functions of MarR homologs.
- The specific stress-related ligand-binding roles of CarR in C. glutamicum remained largely uncharacterized.
Purpose of the Study:
- To characterize the stress-related ligand-binding functions of the C. glutamicum MarR-type regulator, CarR (C. glutamicum antibiotic-responding regulator).
- To elucidate the regulatory mechanisms by which CarR influences gene expression in response to stress.
- To determine the contribution of CarR-mediated gene regulation to cellular stress resistance.
Main Methods:
- Investigated CarR's regulation of the carR-uspA operon, ncgl2885 (decE), and the ncgl2882-ncgl2884 operon (peptidoglycan synthesis operon, PSO).
- Utilized in vivo expression studies with stress-associated ligands (penicillin, streptomycin) and in vitro DNA-binding assays.
- Analyzed the impact of specific conserved residues on CarR's ligand binding and regulatory activity.
Main Results:
- CarR negatively regulates the carR-uspA operon and decE, while positively regulating the PSO operon.
- Stress ligands induced expression of carR, uspA, decE, and PSO, and reduced CarR's DNA binding affinity.
- Upregulation of carR, uspA, and PSO correlated with increased resistance to beta-lactam antibiotics and aromatic compounds.
- Six conserved residues in CarR were identified as critical for ligand binding and transcriptional regulation.
Conclusions:
- Ligand binding causes CarR to dissociate from the carR-uspA promoter, derepressing carR and uspA transcription.
- Ligand-free CarR activates PSO expression, contributing to C. glutamicum stress resistance.
- CarR mediates stress response through ligand-induced conformational changes, not cysteine oxidation.
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