title: Molecular analysis of resistance to streptogramin A compounds conferred by the Vga proteins of staphylococci.
abstract: The Vga and Msr resistance determinants, encoded by mobile genetic elements in various staphylococcal strains, belong to a family of ATP-binding cassette (ABC) proteins whose functions and structures are ill defined. Their amino acid sequences are similar to those of proteins involved in the immunity of streptomycetes to the macrolide-lincosamide-streptogramin antibiotics that they produce. Sequence analysis of the genomes of the gram-positive bacteria with low G+C contents revealed that Lmo0919 from Listeria monocytogenes is more closely related to Vga variants than to Msr variants. In the present study we compared the antibiotic resistance profiles conferred by the Vga-like proteins in two staphylococcal hosts. It was shown that Vga(A), the Vga(A) variant [Vga(A)v], and Lmo0919 can confer resistance to lincosamides and streptogramin A compounds, while only Vga(B) is able to increase the level of resistance to pristinamycin, a mixture of streptogramin A and streptogramin B compounds. By using polyclonal antibodies, we found that the Vga(A) protein colocalized with the beta subunit of the F(1)-F(0) ATPase in the membrane fractions of staphylococcal cells. In order to identify functional units in these atypical ABC proteins, such as regions that might be involved in substrate specificity and/or membrane targeting, we analyzed the resistance phenotypes conferred by various plasmids carrying parts or modified versions of the vga(A) gene and we determined the subcellular localization of the gene products. Only polypeptides composed of two ABC domains were detected in the cell membranes. No region of drug specificity was identified. Resistance properties were dependent on the integrities of both Walker B motifs.
authors.affiliation: Unité des Staphylocoques, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris Cedex 15, France. chesneau@pasteur.fr
authors.forename: Olivier
authors.initials: O
authors.lastname: Chesneau
authors.forename: Heidi
authors.initials: H
authors.lastname: Ligeret
authors.forename: Negin
authors.initials: N
authors.lastname: Hosan-Aghaie
authors.forename: Anne
authors.initials: A
authors.lastname: Morvan
authors.forename: Elie
authors.initials: E
authors.lastname: Dassa
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D024881:Drug Resistance, Bacterial; D008969:Molecular Sequence Data; D010641:Phenotype; D013210:Staphylococcus / Q000187:drug effects*; D025364:Streptogramin A / Q000494:pharmacology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; C075964:VgA protein, Staphylococcus aureus; D025364:Streptogramin A
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