Abstract
Stenotrophomonas maltophilia MfsA (Smlt1083) is an efflux pump in the major facilitator superfamily (MFS). Deletion of mfsA renders the strain more susceptible to paraquat, but no alteration in the susceptibility levels of other oxidants is observed. The expression of mfsA is inducible upon challenge with redox cycling/superoxide-generating drug (paraquat, menadione and plumbagin) treatments and is directly regulated by SoxR, which is a transcription regulator and sensor of superoxide-generating agents. Analysis of mfsA expression patterns in wild-type and a soxR mutant suggests that oxidized SoxR functions as a transcription activator of the gene. soxR (smlt1084) is located in a head-to-head fashion with mfsA, and these genes share the -10 motif of their promoter sequences. Purified SoxR specifically binds to the putative mfsA promoter motifs that contain a region that is highly homologous to the consensus SoxR binding site, and mutation of the SoxR binding site abolishes binding of purified SoxR protein. The SoxR box is located between the putative -35 and -10 promoter motifs of mfsA; and this position is typical for a promoter in which SoxR acts as a transcriptional activator. At the soxR promoter, the SoxR binding site covers the transcription start site of the soxR transcript; thus, binding of SoxR auto-represses its own transcription. Taken together, our results reveal for the first time that mfsA is a novel member of the SoxR regulon and that SoxR binds and directly regulates its expression.
Highlights
Stenotrophomonas maltophilia is an aerobic, Gram-negative, opportunistic pathogen that is ubiquitous in the environment
Analysis of the available bacterial genomes unveiled that the mfs and soxR gene organization is found in some proteobacteria and actinobacteria
Based on the classification of major facilitator superfamily (MFS) proteins that was proposed by Pao et al [26] and phylogenic tree analysis, S. maltophilia MfsA is suggested to be an efflux pump that belongs to a subfamily of the drug:H+ antiporter with 14 transmembrane domain subfamily (DHA14)
Summary
Stenotrophomonas maltophilia is an aerobic, Gram-negative, opportunistic pathogen that is ubiquitous in the environment. S. maltophilia is reported to be associated with infections of cystic fibrosis patients and immunocompromised individuals, those who have been admitted in hospitals for a long period. This pathogen causes meningitis, endocarditis, bacteremia and infections of the respiratory, urinary and gastrointestinal tracts. Under normal physiological conditions, binding of reduced SoxR represses soxS transcription, while, under redox stress, binding of oxidized SoxR activates soxS gene expression [14]. We report the contribution of mfsA, which encodes a MFS protein, to the drug resistance of S. maltophilia. The transcription of mfsA is controlled by SoxR, which is a redox cycling drug/superoxide sensor and transcriptional regulator. Because mfsA and soxR have overlapping promoter sequences, binding of SoxR to a single SoxR binding site controls the gene expression of mfsA and soxR, but in different manners
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