Transcriptome analysis of the responses of Staphylococcus aureus to antimicrobial peptides and characterization of the roles of vraDE and vraSR in antimicrobial resistance

Pietiäinen, Milla; François, Patrice; Hyyryläinen, Hanne‐Leena; Tangomo, Manuela; Sass, V. P.; Sahl, Hans‐Georg; Schrenzel, Jacques; Kontinen, Vesa P.

doi:10.1186/1471-2164-10-429

Cited by 102 publications

(102 citation statements)

References 70 publications

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“…Transcriptional response data with hDB3, but also with other antimicrobial peptides (30,34), clearly indicate that induction of the cell wall stress stimulon is the most prominent response of staphylococcal cells to treatment with HDPs. Nevertheless, membrane depolarization to various degrees (mild with hBD3 and rather strong with LL37) and the concomitant impact on energy-consuming cellular processes certainly contribute to killing as reported earlier (36).…”

Section: Discussionmentioning

confidence: 99%

“…A well-studied adaptation mechanism is based on reduction of the negative charge of the bacterial cell surface by introduction of D-alanine into teichoic acids or of L-lysine into phosphatidylglycerol of staphylococcal cell membranes (32,34,46). In Gram-negative organisms, e.g., in Salmonella enterica serovar Typhimurium, a two-component system, PhoPQ, senses the presence of cationic peptides and in response modulates lipopolysaccharide (LPS) structures and other membrane components.…”

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confidence: 99%

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Human β-Defensin 3 Inhibits Cell Wall Biosynthesis in Staphylococci

et al. 2010

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Human β-Defensin 3 Inhibits Cell Wall Biosynthesis in Staphylococci

et al. 2010

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“…Transcription analysis of S. aureus exposed to cell-wall-targeting antibiotics revealed remarkable upregulation of a gene designated sas016, encoding a hypothetical protein (26,32). S. aureus strain BB255, harboring a plasmid containing the sas016 promoter fused to the luciferase reporter gene, was used to test whether EGCG induces a reaction analogous to that caused by cell-wall-targeting antibiotics.…”

Section: Resultsmentioning

confidence: 99%

Epigallocatechin Gallate Induces Upregulation of the Two-Component VraSR System by Evoking a Cell Wall Stress Response in Staphylococcus aureus

Levinger

Bikels-Goshen

Landau

et al. 2012

Appl Environ Microbiol

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We previously found that a short exposure of Staphylococcus aureus to subinhibitory (SI) doses of epigallocatechin gallate (EGCG) results in increased cell wall thickness, adaptation, and enhanced tolerance to cell-wall-targeted antibiotics. In this study, the response to EGCG of sigB and vraSR transcription factor mutants was characterized. We show that in contrast to the results observed for wild-type (WT) strains, an S. aureus 315 vraSR null mutant exposed to SI doses of EGCG did not exhibit increased tolerance to EGCG and oxacillin. A diminished increase in tolerance to ampicillin (from 16-fold to 4-fold) and no change in the magnitude of resistance to vancomycin were observed. Preexposure to EGCG enhanced the tolerance of wild-type and sigB null mutant cells to lysostaphin, but this enhancement was much weaker in the vraSR null mutant. Marked upregulation (about 60-fold) of vraR and upregulation of the peptidoglycan biosynthesis-associated genes murA, murF, and pbp2 (2-, 5-, and 6-fold, respectively) in response to SI doses of EGCG were determined by quantitative reverse transcription-PCR (qRT-PCR). EGCG also induced the promoter of sas016 (encoding a cell wall stress protein of unknown function which is not induced in vraSR null mutants) in a concentration-dependent manner, showing kinetics comparable to those of cell-wall-targeting antibiotics. Taken together, our results suggest that the two-component VraSR system is involved in modulating the cell response to SI doses of EGCG.

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“…Additionally, producer self-resistance against lantibiotics is often mediated by ATP-binding cassette (ABC) transporters, collectively termed LanFEG, consisting of two membrane-spanning subunits and one ATPase, which are encoded in the biosynthetic loci for the respective lantibiotic and whose expression is regulated by a two-component system (TCS) of the same genetic locus (21). Over the last decade, several ABC transporters of a different type have been identified as resistance determinants against peptide antibiotics in nonproducing strains (5,12,32,35,39,41,44,51). The permeases of these transporters share unique domain architecture with 10 transmembrane helices and a large extracellular domain (ECD) of about 200 amino acids between helices 7 and 8.…”

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Coevolution of ABC Transporters and Two-Component Regulatory Systems as Resistance Modules against Antimicrobial Peptides in Firmicutes Bacteria

et al. 2011

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In Firmicutes bacteria, ATP-binding cassette (ABC) transporters have been recognized as important resistance determinants against antimicrobial peptides. Together with neighboring two-component systems (TCSs), which regulate their expression, they form specific detoxification modules. Both the transport permease and sensor kinase components show unusual domain architecture: the permeases contain a large extracellular domain, while the sensor kinases lack an obvious input domain. One of the best-characterized examples is the bacitracin resistance module BceRS-BceAB of Bacillus subtilis. Strikingly, in this system, the ABC transporter and TCS have an absolute mutual requirement for each other in both sensing of and resistance to bacitracin, suggesting a novel mode of signal transduction in which the transporter constitutes the actual sensor. We identified over 250 such BceAB-like ABC transporters in the current databases. They occurred almost exclusively in Firmicutes bacteria, and 80% of the transporters were associated with a BceRS-like TCS. Phylogenetic analyses of the permease and sensor kinase components revealed a tight evolutionary correlation. Our findings suggest a direct regulatory interaction between the ABC transporters and TCSs, mediating communication between both components. Based on their observed coclustering and conservation of response regulator binding sites, we could identify putative corresponding two-component systems for transporters lacking a regulatory system in their immediate neighborhood. Taken together, our results show that these types of ABC transporters and TCSs have coevolved to form self-sufficient detoxification modules against antimicrobial peptides, widely distributed among Firmicutes bacteria.

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Transcriptome analysis of the responses of Staphylococcus aureus to antimicrobial peptides and characterization of the roles of vraDE and vraSR in antimicrobial resistance

Cited by 102 publications

References 70 publications

Human β-Defensin 3 Inhibits Cell Wall Biosynthesis in Staphylococci

Human β-Defensin 3 Inhibits Cell Wall Biosynthesis in Staphylococci

Epigallocatechin Gallate Induces Upregulation of the Two-Component VraSR System by Evoking a Cell Wall Stress Response in Staphylococcus aureus

Coevolution of ABC Transporters and Two-Component Regulatory Systems as Resistance Modules against Antimicrobial Peptides in Firmicutes Bacteria

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