HTH-type transcriptional repressor LfrR (LfrR)

HTH-type transcriptional repressor LfrR is a member of the TetR family of regulators, primarily identified and characterized in Mycobacterium smegmatis [1, 2]. It serves as the primary negative regulator of the lfrRA operon, which encodes the LfrA multidrug efflux pump, a major facilitator superfamily (MFS) transporter [2, 4]. In the absence of inducing signals, LfrR homodimers bind to a specific operator sequence in the promoter region, sterically hindering RNA polymerase and repressing transcription [2, 3]. This repression is relieved when LfrR binds to various small-molecule ligands, such as cationic dyes (e.g., ethidium bromide, acriflavine, proflavine) and certain antibiotics like fluoroquinolones [2, 3]. Ligand binding induces a conformational change that reduces the protein's affinity for DNA, leading to the overexpression of the LfrA pump and subsequent extrusion of toxic compounds from the cell [3, 4]. As a key mediator of intrinsic multidrug resistance in mycobacteria, LfrR is a significant target for studying bacterial adaptation and developing strategies to sensitize pathogens to existing antibiotics [1, 2]. Structural studies have revealed that LfrR possesses a high degree of conformational plasticity, allowing it to recognize a broad range of structurally diverse ligands [3]. Mutations in the lfrR gene can lead to constitutive expression of the efflux pump, further enhancing the multidrug-resistant phenotype of the bacteria [2]. Understanding the regulatory network of LfrR provides insights into the evolution of antibiotic resistance in clinically relevant mycobacteria like Mycobacterium tuberculosis [1, 4].

Other names

MSMEG_6223TetR family transcriptional repressor LfrRLfrRA repressor

Ligand-induced dissociation from DNA leading to the induction of the LfrA multidrug efflux pump