title: LmrCD is a major multidrug resistance transporter in Lactococcus lactis.
abstract: When Lactococcus lactis is challenged with drugs it displays a multidrug resistance (MDR) phenotype. In silico analysis of the genome of L. lactis indicates the presence of at least 40 putative MDR transporters, of which only four, i.e. the ABC transporters LmrA, LmrC and LmrD, and the major facilitator LmrP, have been experimentally associated with the MDR. To understand the molecular basis of the MDR phenotype in L. lactis, we have performed a global transcriptome analysis comparing four independently isolated drug-resistant strains of L. lactis with the wild-type strain. The results show a strong and consistent upregulation of the lmrC and lmrD genes in all four strains, while the mRNA levels of other putative MDR transporters were not significantly altered. Deletion of lmrCD renders L. lactis sensitive to several toxic compounds, and this phenotype is associated with a reduced ability to secrete these compounds. Another gene, which is strongly upregulated in all mutant strains, specifies LmrR (YdaF), a local transcriptional repressor of lmrCD that belongs to the PadR family of transcriptional regulators and that binds to the promoter region of lmrCD. These results demonstrate that the heterodimeric MDR ABC transporter LmrCD is a major determinant of both acquired and intrinsic drug resistance of L. lactis.
authors.affiliation: Department of Molecular Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Kerklaan 30, NL-9751 Haren, the Netherlands.
authors.forename: Jacek
authors.initials: J
authors.lastname: Lubelski
authors.forename: Anne
authors.initials: A
authors.lastname: de Jong
authors.forename: Ronald
authors.initials: R
authors.lastname: van Merkerk
authors.forename: Herfita
authors.initials: H
authors.lastname: Agustiandari
authors.forename: Oscar P
authors.initials: OP
authors.lastname: Kuipers
authors.forename: Jan
authors.initials: J
authors.lastname: Kok
authors.forename: Arnold J M
authors.initials: AJ
authors.lastname: Driessen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D024901:Drug Resistance, Multiple, Bacterial / Q000502:physiology*; D017353:Gene Deletion; D015964:Gene Expression Regulation, Bacterial; D013294:Lactococcus lactis / Q000187:drug effects* / Q000502:physiology*; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic
chemical_list: D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513418:LmrC protein, Lactococcus lactis; C513419:LmrD protein, Lactococcus lactis