A New Evolutionary Variant of the Streptogramin A Resistance Protein, Vga(A)
            <sub>LC</sub>
            , from
            <i>Staphylococcus haemolyticus</i>
            with Shifted Substrate Specificity towards Lincosamides

Novotná, Gabriela Balíková; Janata, Jiřı́

doi:10.1128/aac.00799-06

Cited by 77 publications

(80 citation statements)

References 45 publications

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“…Two studies showed decreased accumulations of radiolabeled erythromycin and lincomycin in the presence of Msr(A) and Vga(A) LC , respectively (18,19). These proteins might recruit a membrane-spanning protein to cause active efflux of antibiotics, but no membrane partners have been identified yet (18,19). Alternatively, a ribosome-related mechanism of resistance, such as ribosomal protection, could also be hypothesized.…”

Section: Resultsmentioning

confidence: 99%

“…Although Lsa(A) and other members of the class 2 ABC proteins are presumed to function as efflux pumps, the biochemical basis of resistance remains unclear. Two studies showed decreased accumulations of radiolabeled erythromycin and lincomycin in the presence of Msr(A) and Vga(A) LC , respectively (18,19). These proteins might recruit a membrane-spanning protein to cause active efflux of antibiotics, but no membrane partners have been identified yet (18,19).…”

Section: Resultsmentioning

confidence: 99%

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Cross-Resistance to Lincosamides, Streptogramins A, and Pleuromutilins Due to the lsa (C) Gene in Streptococcus agalactiae UCN70

Malbruny

Werno

Murdoch

et al. 2011

Antimicrob Agents Chemother

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Streptococcus agalactiae UCN70, isolated from a vaginal swab obtained in New Zealand, is resistant to lincosamides and streptogramins A (LS A phenotype) and also to tiamulin (a pleuromutilin). By whole-genome sequencing, we identified a 5,224-bp chromosomal extra-element that comprised a 1,479-bp open reading frame coding for an ABC protein (492 amino acids) 45% identical to Lsa(A), a protein related to intrinsic LS A resistance in Enterococcus faecalis. Expression of this novel gene, named lsa(C), in S. agalactiae BM132 after cloning led to an increase in MICs of lincomycin (0.06 to 4 g/ml), clindamycin (0.03 to 2 g/ml), dalfopristin (2 to >32 g/ml), and tiamulin (0.12 to 32 g/ml), whereas no change in MICs of erythromycin (0.06 g/ml), azithromycin (0.03 g/ml), spiramycin (0.25 g/ml), telithromycin (0.03 g/ml), and quinupristin (8 g/ml) was observed. The phenotype was renamed the LS A P phenotype on the basis of cross-resistance to lincosamides, streptogramins A, and pleuromutilins. This gene was also identified in similar genetic environments in 17 other S. agalactiae clinical isolates from New Zealand exhibiting the same LS A P phenotype, whereas it was absent in susceptible S. agalactiae strains. Interestingly, this extra-element was bracketed by a 7-bp duplication of a target site (ATTAGAA), suggesting that this structure was likely a mobile genetic element. In conclusion, we identified a novel gene, lsa(C), responsible for the acquired LS A P resistance phenotype in S. agalactiae. Dissection of the biochemical basis of resistance, as well as demonstration of in vitro mobilization of lsa(C), remains to be performed.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Cross-Resistance to Lincosamides, Streptogramins A, and Pleuromutilins Due to the lsa (C) Gene in Streptococcus agalactiae UCN70

Malbruny

Werno

Murdoch

et al. 2011

Antimicrob Agents Chemother

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“…Very recently, a Vga(A) LC variant conferring in vivo an increased resistance to lincosamides and a reduced resistance to SgA, was isolated from Staphylococcus haemolyticus (47). As compared with Vga(A), this variant displays four sequence changes that affect amino acids located within the linker region and responsible for the altered substrate specificity.…”

Section: Discussionmentioning

confidence: 99%

ATP Hydrolysis and Pristinamycin IIA Inhibition of the Staphylococcus aureus Vga(A), a Dual ABC Protein Involved in Streptogramin A Resistance

Jacquet

Girard

Ramaen

et al. 2008

Journal of Biological Chemistry

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In Gram-positive bacteria, a large subfamily of dual ATPbinding cassette proteins confers acquired or intrinsic resistance to macrolide, lincosamide, and streptogramin antibiotics by a far from well understood mechanism. Here, we report the first biochemical characterization of one such protein, Vga(A), which is involved in streptogramin A (SgA) resistance among staphylococci. Vga(A) is composed of two nucleotide-binding domains (NBDs), separated by a charged linker, with a C-terminal extension and without identified transmembrane domains. Highly purified Vga(A) displays a strong ATPase activity (K m ‫؍‬ 78 M, V m ‫؍‬ 6.8 min ؊1 ) that was hardly inhibited by orthovanadate. Using mutants of the conserved catalytic glutamate residues, the two NBDs of Vga(A) were shown to contribute unequally to the total ATPase activity, the mutation at NBD2 being more detrimental than the other. ATPase activity of both catalytic sites was essential for Vga(A) biological function because each single Glu mutant was unable to confer SgA resistance in the staphylococcal host. Of great interest, Vga(A) ATPase was specifically inhibited in a non-competitive manner by the SgA substrate, pristinamycin IIA (PIIA). A deletion of the last 18 amino acids of Vga(A) slightly affected the ATPase activity without modifying the PIIA inhibition values. In contrast, this deletion reduced 4-fold the levels of SgA resistance. Altogether, our results suggest a role for the C terminus in regulation of the SgA antibiotic resistance mechanism conferred by Vga(A) and demonstrate that this dual ATP-binding cassette protein interacts directly and specifically with PIIA, its cognate substrate.

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“…Given that no interacting TM domains have been identified in this family, substrate specificity may be determined by the ABC proteins. Indeed, a Vga(A) variant with a four-amino-acid substitution in the linker between the two ABC domains shifted the drug resistance profile from streptogramin A to lincosamides (337).…”

Section: Art Family Of Proteins With Diverse Functionsmentioning

confidence: 99%

Structure, Function, and Evolution of Bacterial ATP-Binding Cassette Systems

Davidson

Dassa

Orelle

et al. 2008

Microbiol Mol Biol Rev

1,139

1,137

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SUMMARY ATP-binding cassette (ABC) systems are universally distributed among living organisms and function in many different aspects of bacterial physiology. ABC transporters are best known for their role in the import of essential nutrients and the export of toxic molecules, but they can also mediate the transport of many other physiological substrates. In a classical transport reaction, two highly conserved ATP-binding domains or subunits couple the binding/hydrolysis of ATP to the translocation of particular substrates across the membrane, through interactions with membrane-spanning domains of the transporter. Variations on this basic theme involve soluble ABC ATP-binding proteins that couple ATP hydrolysis to nontransport processes, such as DNA repair and gene expression regulation. Insights into the structure, function, and mechanism of action of bacterial ABC proteins are reported, based on phylogenetic comparisons as well as classic biochemical and genetic approaches. The availability of an increasing number of high-resolution structures has provided a valuable framework for interpretation of recent studies, and realistic models have been proposed to explain how these fascinating molecular machines use complex dynamic processes to fulfill their numerous biological functions. These advances are also important for elucidating the mechanism of action of eukaryotic ABC proteins, because functional defects in many of them are responsible for severe human inherited diseases.

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A New Evolutionary Variant of the Streptogramin A Resistance Protein, Vga(A) _LC , from Staphylococcus haemolyticus with Shifted Substrate Specificity towards Lincosamides

Cited by 77 publications

References 45 publications

Cross-Resistance to Lincosamides, Streptogramins A, and Pleuromutilins Due to the lsa (C) Gene in Streptococcus agalactiae UCN70

Cross-Resistance to Lincosamides, Streptogramins A, and Pleuromutilins Due to the lsa (C) Gene in Streptococcus agalactiae UCN70

ATP Hydrolysis and Pristinamycin IIA Inhibition of the Staphylococcus aureus Vga(A), a Dual ABC Protein Involved in Streptogramin A Resistance

Structure, Function, and Evolution of Bacterial ATP-Binding Cassette Systems

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A New Evolutionary Variant of the Streptogramin A Resistance Protein, Vga(A) LC , from Staphylococcus haemolyticus with Shifted Substrate Specificity towards Lincosamides

Cited by 77 publications

References 45 publications

Cross-Resistance to Lincosamides, Streptogramins A, and Pleuromutilins Due to the lsa (C) Gene in Streptococcus agalactiae UCN70

Cross-Resistance to Lincosamides, Streptogramins A, and Pleuromutilins Due to the lsa (C) Gene in Streptococcus agalactiae UCN70

ATP Hydrolysis and Pristinamycin IIA Inhibition of the Staphylococcus aureus Vga(A), a Dual ABC Protein Involved in Streptogramin A Resistance

Structure, Function, and Evolution of Bacterial ATP-Binding Cassette Systems

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Product

Resources

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A New Evolutionary Variant of the Streptogramin A Resistance Protein, Vga(A) _LC , from Staphylococcus haemolyticus with Shifted Substrate Specificity towards Lincosamides