The AGXX (R) Antimicrobial Coating Causes a Thiol-Specific Oxidative Stress Response and Protein S-bacillithiolation in Staphylococcus aureus

Van Loi V, Busche T, Preuss T, Kalinowski J, Bernhardt J, Antelmann H (2018)

Zeitschriftenaufsatz | Veröffentlicht | Englisch
Es wurden keine Dateien hochgeladen. Nur Publikationsnachweis!
Van Loi, Vu; Busche, Tobias; Preuss, Thalia; Kalinowski, JörnUniBi; Bernhardt, Jorg; Antelmann, Haike
Abstract / Bemerkung
Multidrug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) pose an increasing health burden and demand alternative antimicrobials to treat bacterial infections. The surface coating AGXX (R) is a novel broad-spectrum antimicrobial composed of two transition metals, silver and ruthenium that can be electroplated on various surfaces, such as medical devices and implants. AGXX (R) has been shown to kill nosocomial and waterborne pathogens by production of reactive oxygen species (ROS), but the effect of AGXX (R) on the bacterial redox balance has not been demonstrated. Since treatment options for MRSA infections are limited, ROS-producing agents are attractive alternatives to combat multi-resistant strains. In this work, we used RNA-seq transcriptomics, redox biosensor measurements and phenotype analyses to study the mode of action of AGXX (R) microparticles in S. aureus USA300. Using growth and survival assays, the growth-inhibitory amount of AGXX (R) microparticles was determined as 5 mu g/ml. In the RNA-seq transcriptome, AGXX (R) caused a strong thiol-specific oxidative stress response and protein damage as revealed by the induction of the PerR, HypR, QsrR, MhqR, CstR, CtsR, and HrcA regulons. The derepression of the Fur, Zur, and CsoR regulons indicates that AGXX (R) also interferes with the metal ion homeostasis inducing Fe-2(+)- and Zn-2(+)-starvation responses as well as export systems for toxic Ag+ ions. The induction of the SigB and GraRS regulons reveals also cell wall and general stress responses. AGXX (R). stress was further shown to cause protein S-bacillithiolation, protein aggregation and an oxidative shift in the bacillithiol (BSH) redox potential. In phenotype assays, BSH and the HypR-controlled disulfide reductase MerA were required for protection against ROS produced under AGXX (R) stress in S. aureus. Altogether, our study revealed a strong thiol-reactive mode of action of AGXX (R) in S. aureus USA300 resulting in an increased BSH redox potential and protein S-bacillithiolation.
Page URI


Van Loi V, Busche T, Preuss T, Kalinowski J, Bernhardt J, Antelmann H. The AGXX (R) Antimicrobial Coating Causes a Thiol-Specific Oxidative Stress Response and Protein S-bacillithiolation in Staphylococcus aureus. FRONTIERS IN MICROBIOLOGY. 2018;9: 3037.
Van Loi, V., Busche, T., Preuss, T., Kalinowski, J., Bernhardt, J., & Antelmann, H. (2018). The AGXX (R) Antimicrobial Coating Causes a Thiol-Specific Oxidative Stress Response and Protein S-bacillithiolation in Staphylococcus aureus. FRONTIERS IN MICROBIOLOGY, 9, 3037. doi:10.3389/fmicb.2018.03037
Van Loi, V., Busche, T., Preuss, T., Kalinowski, J., Bernhardt, J., and Antelmann, H. (2018). The AGXX (R) Antimicrobial Coating Causes a Thiol-Specific Oxidative Stress Response and Protein S-bacillithiolation in Staphylococcus aureus. FRONTIERS IN MICROBIOLOGY 9:3037.
Van Loi, V., et al., 2018. The AGXX (R) Antimicrobial Coating Causes a Thiol-Specific Oxidative Stress Response and Protein S-bacillithiolation in Staphylococcus aureus. FRONTIERS IN MICROBIOLOGY, 9: 3037.
V. Van Loi, et al., “The AGXX (R) Antimicrobial Coating Causes a Thiol-Specific Oxidative Stress Response and Protein S-bacillithiolation in Staphylococcus aureus”, FRONTIERS IN MICROBIOLOGY, vol. 9, 2018, : 3037.
Van Loi, V., Busche, T., Preuss, T., Kalinowski, J., Bernhardt, J., Antelmann, H.: The AGXX (R) Antimicrobial Coating Causes a Thiol-Specific Oxidative Stress Response and Protein S-bacillithiolation in Staphylococcus aureus. FRONTIERS IN MICROBIOLOGY. 9, : 3037 (2018).
Van Loi, Vu, Busche, Tobias, Preuss, Thalia, Kalinowski, Jörn, Bernhardt, Jorg, and Antelmann, Haike. “The AGXX (R) Antimicrobial Coating Causes a Thiol-Specific Oxidative Stress Response and Protein S-bacillithiolation in Staphylococcus aureus”. FRONTIERS IN MICROBIOLOGY 9 (2018): 3037.

1 Zitation in Europe PMC

Daten bereitgestellt von Europe PubMed Central.

Staphylococcus aureus Uses the Bacilliredoxin (BrxAB)/Bacillithiol Disulfide Reductase (YpdA) Redox Pathway to Defend Against Oxidative Stress Under Infections.
Linzner N, Loi VV, Fritsch VN, Tung QN, Stenzel S, Wirtz M, Hell R, Hamilton CJ, Tedin K, Fulde M, Antelmann H., Front Microbiol 10(), 2019
PMID: 31275277

79 References

Daten bereitgestellt von Europe PubMed Central.

mosR, a novel transcriptional regulator of hypoxia and virulence in Mycobacterium tuberculosis.
Abomoelak B, Hoye EA, Chi J, Marcus SA, Laval F, Bannantine JP, Ward SK, Daffe M, Liu HD, Talaat AM., J. Bacteriol. 191(19), 2009
PMID: 19648248
Staphylococcus aureus: a well-armed pathogen.
Archer GL., Clin. Infect. Dis. 26(5), 1998
PMID: 9597249
Epidemiology of methicillin-resistant Staphylococcus aureus.
Boucher HW, Corey GR., Clin. Infect. Dis. 46 Suppl 5(), 2008
PMID: 18462089
The Role of Bacillithiol in Gram-Positive Firmicutes.
Chandrangsu P, Loi VV, Antelmann H, Helmann JD., Antioxid. Redox Signal. 28(6), 2017
PMID: 28301954
Metal homeostasis and resistance in bacteria.
Chandrangsu P, Rensing C, Helmann JD., Nat. Rev. Microbiol. 15(6), 2017
PMID: 28344348
Preparation and characterization of ruthenium films via an electroless deposition route
Chen J.-Y., Wang L.-Y., Wu P.-W.., 2010
An oxidation-sensing mechanism is used by the global regulator MgrA in Staphylococcus aureus.
Chen PR, Bae T, Williams WA, Duguid EM, Rice PA, Schneewind O, He C., Nat. Chem. Biol. 2(11), 2006
PMID: 16980961
Redox signaling in human pathogens.
Chen PR, Brugarolas P, He C., Antioxid. Redox Signal. 14(6), 2010
PMID: 20578795
A new oxidative sensing and regulation pathway mediated by the MgrA homologue SarZ in Staphylococcus aureus.
Chen PR, Nishida S, Poor CB, Cheng A, Bae T, Kuechenmeister L, Dunman PM, Missiakas D, He C., Mol. Microbiol. 71(1), 2008
PMID: 19007410
Protein S-mycothiolation functions as redox-switch and thiol protection mechanism in Corynebacterium glutamicum under hypochlorite stress.
Chi BK, Busche T, Van Laer K, Basell K, Becher D, Clermont L, Seibold GM, Persicke M, Kalinowski J, Messens J, Antelmann H., Antioxid. Redox Signal. 20(4), 2013
PMID: 23886307
S-bacillithiolation protects against hypochlorite stress in Bacillus subtilis as revealed by transcriptomics and redox proteomics.
Chi BK, Gronau K, Mader U, Hessling B, Becher D, Antelmann H., Mol. Cell Proteomics 10(11), 2011
PMID: 21749987
S-bacillithiolation protects conserved and essential proteins against hypochlorite stress in firmicutes bacteria.
Chi BK, Roberts AA, Huyen TT, Basell K, Becher D, Albrecht D, Hamilton CJ, Antelmann H., Antioxid. Redox Signal. 18(11), 2012
PMID: 22938038
Stress response of a clinical Enterococcus faecalis isolate subjected to a novel antimicrobial surface coating.
Clauss-Lendzian E, Vaishampayan A, de Jong A, Landau U, Meyer C, Kok J, Grohmann E., Microbiol. Res. 207(), 2017
PMID: 29458868
Imaging dynamic redox changes in mammalian cells with green fluorescent protein indicators.
Dooley CT, Dore TM, Hanson GT, Jackson WC, Remington SJ, Tsien RY., J. Biol. Chem. 279(21), 2004
PMID: 14985369
Peroxiredoxins in bacterial antioxidant defense.
Dubbs JM, Mongkolsuk S., Subcell. Biochem. 44(), 2007
PMID: 18084893
The Staphylococcus aureus "superbug".
Foster TJ., J. Clin. Invest. 114(12), 2004
PMID: 15599392
Clp ATPases are required for stress tolerance, intracellular replication and biofilm formation in Staphylococcus aureus.
Frees D, Chastanet A, Qazi S, Sorensen K, Hill P, Msadek T, Ingmer H., Mol. Microbiol. 54(5), 2004
PMID: 15554981
Alternative roles of ClpX and ClpP in Staphylococcus aureus stress tolerance and virulence.
Frees D, Qazi SN, Hill PJ, Ingmer H., Mol. Microbiol. 48(6), 2003
PMID: 12791139
Clp ATPases and ClpP proteolytic complexes regulate vital biological processes in low GC, Gram-positive bacteria.
Frees D, Savijoki K, Varmanen P, Ingmer H., Mol. Microbiol. 63(5), 2007
PMID: 17302811
Metallic copper as an antimicrobial surface.
Grass G, Rensing C, Solioz M., Appl. Environ. Microbiol. 77(5), 2010
PMID: 21193661
Pseudomonas aeruginosa defense systems against microbicidal oxidants.
Groitl B, Dahl JU, Schroeder JW, Jakob U., Mol. Microbiol. 106(3), 2017
PMID: 28795780
Control of copper resistance and inorganic sulfur metabolism by paralogous regulators in Staphylococcus aureus.
Grossoehme N, Kehl-Fie TE, Ma Z, Adams KW, Cowart DM, Scott RA, Skaar EP, Giedroc DP., J. Biol. Chem. 286(15), 2011
PMID: 21339296
Molecular basis for resistance to silver cations in Salmonella.
Gupta A, Matsui K, Lo JF, Silver S., Nat. Med. 5(2), 1999
PMID: 9930866
New antimicrobial contact catalyst killing antibiotic resistant clinical and waterborne pathogens.
Guridi A, Diederich AK, Aguila-Arcos S, Garcia-Moreno M, Blasi R, Broszat M, Schmieder W, Clauss-Lendzian E, Sakinc-Gueler T, Andrade R, Alkorta I, Meyer C, Landau U, Grohmann E., Mater Sci Eng C Mater Biol Appl 50(), 2015
PMID: 25746238
Enhanced antibacterial activity of silver-ruthenium coated hollow microparticles.
Heiss A, Freisinger B, Held-Fohn E., Biointerphases 12(5), 2017
PMID: 29212331
Conformational analysis and chemical reactivity of the multidomain sulfurtransferase, Staphylococcus aureus CstA.
Higgins KA, Peng H, Luebke JL, Chang FM, Giedroc DP., Biochemistry 54(14), 2015
PMID: 25793461
Subtle genetic changes enhance virulence of methicillin resistant and sensitive Staphylococcus aureus.
Highlander SK, Hulten KG, Qin X, Jiang H, Yerrapragada S, Mason EO Jr, Shang Y, Williams TM, Fortunov RM, Liu Y, Igboeli O, Petrosino J, Tirumalai M, Uzman A, Fox GE, Cardenas AM, Muzny DM, Hemphill L, Ding Y, Dugan S, Blyth PR, Buhay CJ, Dinh HH, Hawes AC, Holder M, Kovar CL, Lee SL, Liu W, Nazareth LV, Wang Q, Zhou J, Kaplan SL, Weinstock GM., BMC Microbiol. 7(), 2007
PMID: 17986343
ReadXplorer 2-detailed read mapping analysis and visualization from one single source.
Hilker R, Stadermann KB, Schwengers O, Anisiforov E, Jaenicke S, Weisshaar B, Zimmermann T, Goesmann A., Bioinformatics 32(24), 2016
PMID: 27540267
Thiol-based redox switches in prokaryotes.
Hillion M, Antelmann H., Biol. Chem. 396(5), 2015
PMID: 25720121
Monitoring global protein thiol-oxidation and protein S-mycothiolation in Mycobacterium smegmatis under hypochlorite stress.
Hillion M, Bernhardt J, Busche T, Rossius M, Maaß S, Becher D, Rawat M, Wirtz M, Hell R, Ruckert C, Kalinowski J, Antelmann H., Sci Rep 7(1), 2017
PMID: 28446771
PerR controls oxidative stress resistance and iron storage proteins and is required for virulence in Staphylococcus aureus.
Horsburgh MJ, Clements MO, Crossley H, Ingham E, Foster SJ., Infect. Immun. 69(6), 2001
PMID: 11349039
Zinc center as redox switch--new function for an old motif.
Ilbert M, Graf PC, Jakob U., Antioxid. Redox Signal. 8(5-6), 2006
PMID: 16771674
Protein S-Bacillithiolation Functions in Thiol Protection and Redox Regulation of the Glyceraldehyde-3-Phosphate Dehydrogenase Gap in Staphylococcus aureus Under Hypochlorite Stress.
Imber M, Huyen NTT, Pietrzyk-Brzezinska AJ, Loi VV, Hillion M, Bernhardt J, Tharichen L, Kolsek K, Saleh M, Hamilton CJ, Adrian L, Grater F, Wahl MC, Antelmann H., Antioxid. Redox Signal. 28(6), 2017
PMID: 27967218
The aldehyde dehydrogenase AldA contributes to the hypochlorite defense and is redox-controlled by protein S-bacillithiolation in Staphylococcus aureus.
Imber M, Loi VV, Reznikov S, Fritsch VN, Pietrzyk-Brzezinska AJ, Prehn J, Hamilton C, Wahl MC, Bronowska AK, Antelmann H., Redox Biol 15(), 2018
PMID: 29433022
Redox regulation by reversible protein S-thiolation in Gram-positive bacteria.
Imber M, Pietrzyk-Brzezinska AJ, Antelmann H., Redox Biol 20(), 2018
PMID: 30308476
Staphylococcus aureus PerR Is a Hypersensitive Hydrogen Peroxide Sensor using Iron-mediated Histidine Oxidation.
Ji CJ, Kim JH, Won YB, Lee YE, Choi TW, Ju SY, Youn H, Helmann JD, Lee JW., J. Biol. Chem. 290(33), 2015
PMID: 26134568
Fast gapped-read alignment with Bowtie 2.
Langmead B, Salzberg SL., Nat. Methods 9(4), 2012
PMID: 22388286
The Sequence Alignment/Map format and SAMtools.
Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R; 1000 Genome Project Data Processing Subgroup., Bioinformatics 25(16), 2009
PMID: 19505943
Antibiotic resistance in staphylococci.
Livermore DM., Int. J. Antimicrob. Agents 16 Suppl 1(), 2000
PMID: 11137402
Redox-Sensing Under Hypochlorite Stress and Infection Conditions by the Rrf2-Family Repressor HypR in Staphylococcus aureus.
Loi VV, Busche T, Tedin K, Bernhardt J, Wollenhaupt J, Huyen NTT, Weise C, Kalinowski J, Wahl MC, Fulde M, Antelmann H., Antioxid. Redox Signal. 29(7), 2018
PMID: 29237286
Real-Time Imaging of the Bacillithiol Redox Potential in the Human Pathogen Staphylococcus aureus Using a Genetically Encoded Bacilliredoxin-Fused Redox Biosensor.
Loi VV, Harms M, Muller M, Huyen NTT, Hamilton CJ, Hochgrafe F, Pane-Farre J, Antelmann H., Antioxid. Redox Signal. 26(15), 2016
PMID: 27462976
Redox regulation by reversible protein S-thiolation in bacteria.
Loi VV, Rossius M, Antelmann H., Front Microbiol 6(), 2015
PMID: 25852656
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.
Love MI, Huber W, Anders S., Genome Biol. 15(12), 2014
PMID: 25516281
Staphylococcus aureus infections.
Lowy FD., N. Engl. J. Med. 339(8), 1998
PMID: 9709046
The CsoR-like sulfurtransferase repressor (CstR) is a persulfide sensor in Staphylococcus aureus.
Luebke JL, Shen J, Bruce KE, Kehl-Fie TE, Peng H, Skaar EP, Giedroc DP., Mol. Microbiol. 94(6), 2014
PMID: 25318663
Staphylococcus aureus Transcriptome Architecture: From Laboratory to Infection-Mimicking Conditions.
Mader U, Nicolas P, Depke M, Pane-Farre J, Debarbouille M, van der Kooi-Pol MM, Guerin C, Derozier S, Hiron A, Jarmer H, Leduc A, Michalik S, Reilman E, Schaffer M, Schmidt F, Bessieres P, Noirot P, Hecker M, Msadek T, Volker U, van Dijl JM., PLoS Genet. 12(4), 2016
PMID: 27035918
Silver as an antimicrobial: facts and gaps in knowledge.
Maillard JY, Hartemann P., Crit. Rev. Microbiol. 39(4), 2012
PMID: 22928774
Data visualization in environmental proteomics.
Mehlan H, Schmidt F, Weiss S, Schuler J, Fuchs S, Riedel K, Bernhardt J., Proteomics 13(18-19), 2013
PMID: 23913834
Metal ion homeostasis in Bacillus subtilis.
Moore CM, Helmann JD., Curr. Opin. Microbiol. 8(2), 2005
PMID: 15802251
Detoxification of toxins by bacillithiol in Staphylococcus aureus.
Newton GL, Fahey RC, Rawat M., Microbiology (Reading, Engl.) 158(Pt 4), 2012
PMID: 22262099
Identifying and Tackling Emergent Vulnerability in Drug-Resistant Mycobacteria.
Padiadpu J, Baloni P, Anand K, Munshi M, Thakur C, Mohan A, Singh A, Chandra N., ACS Infect Dis 2(9), 2016
PMID: 27759382
Clinical relevance of the ESKAPE pathogens.
Pendleton JN, Gorman SP, Gilmore BF., Expert Rev Anti Infect Ther 11(3), 2013
PMID: 23458769
Sulfide Homeostasis and Nitroxyl Intersect via Formation of Reactive Sulfur Species in Staphylococcus aureus.
Peng H, Shen J, Edmonds KA, Luebke JL, Hickey AK, Palmer LD, Chang FJ, Bruce KA, Kehl-Fie TE, Skaar EP, Giedroc DP., mSphere 2(3), 2017
PMID: 28656172
Activation of the alternative sigma factor SigB of Staphylococcus aureus following internalization by epithelial cells - an in vivo proteomics perspective.
Pfortner H, Burian MS, Michalik S, Depke M, Hildebrandt P, Dhople VM, Pane-Farre J, Hecker M, Schmidt F, Volker U., Int. J. Med. Microbiol. 304(2), 2013
PMID: 24480029
Redox Sensing by Fe2+ in Bacterial Fur Family Metalloregulators.
Pinochet-Barros A, Helmann JD., Antioxid. Redox Signal. 29(18), 2017
PMID: 28938859
Importance of bacillithiol in the oxidative stress response of Staphylococcus aureus.
Posada AC, Kolar SL, Dusi RG, Francois P, Roberts AA, Hamilton CJ, Liu GY, Cheung A., Infect. Immun. 82(1), 2013
PMID: 24166956
Distribution and infection-related functions of bacillithiol in Staphylococcus aureus.
Pother DC, Gierok P, Harms M, Mostertz J, Hochgrafe F, Antelmann H, Hamilton CJ, Borovok I, Lalk M, Aharonowitz Y, Hecker M., Int. J. Med. Microbiol. 303(3), 2013
PMID: 23517692
RNAIII-independent target gene control by the agr quorum-sensing system: insight into the evolution of virulence regulation in Staphylococcus aureus.
Queck SY, Jameson-Lee M, Villaruz AE, Bach TH, Khan BA, Sturdevant DE, Ricklefs SM, Li M, Otto M., Mol. Cell 32(1), 2008
PMID: 18851841
Staphylococcus aureus CstB Is a Novel Multidomain Persulfide Dioxygenase-Sulfurtransferase Involved in Hydrogen Sulfide Detoxification.
Shen J, Keithly ME, Armstrong RN, Higgins KA, Edmonds KA, Giedroc DP., Biochemistry 54(29), 2015
PMID: 26177047
Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance.
Sun F, Ding Y, Ji Q, Liang Z, Deng X, Wong CC, Yi C, Zhang L, Xie S, Alvarez S, Hicks LM, Luo C, Jiang H, Lan L, He C., Proc. Natl. Acad. Sci. U.S.A. 109(38), 2012
PMID: 22927394
Differential gene expression in response to phenol and catechol reveals different metabolic activities for the degradation of aromatic compounds in Bacillus subtilis.
Tam le T, Eymann C, Albrecht D, Sietmann R, Schauer F, Hecker M, Antelmann H., Environ. Microbiol. 8(8), 2006
PMID: 16872404
The C terminus of sigma(32) is not essential for degradation by FtsH.
Tomoyasu T, Arsene F, Ogura T, Bukau B., J. Bacteriol. 183(20), 2001
PMID: 11566990
A Novel Antimicrobial Coating Represses Biofilm and Virulence-Related Genes in Methicillin-Resistant Staphylococcus aureus.
Vaishampayan A, de Jong A, Wight DJ, Kok J, Grohmann E., Front Microbiol 9(), 2018
PMID: 29497410
Antibacterial Metallic Touch Surfaces.
Villapun VM, Dover LG, Cross A, Gonzalez S., Materials (Basel) 9(9), 2016
PMID: 28773856
Cloning, sequencing, and molecular analysis of the dnaK locus from Bacillus subtilis.
Wetzstein M, Volker U, Dedio J, Lobau S, Zuber U, Schiesswohl M, Herget C, Hecker M, Schumann W., J. Bacteriol. 174(10), 1992
PMID: 1339421
Bleach activates a redox-regulated chaperone by oxidative protein unfolding.
Winter J, Ilbert M, Graf PC, Ozcelik D, Jakob U., Cell 135(4), 2008
PMID: 19013278
Redox reactions and microbial killing in the neutrophil phagosome.
Winterbourn CC, Kettle AJ., Antioxid. Redox Signal. 18(6), 2012
PMID: 22881869
Reactive Oxygen Species and Neutrophil Function.
Winterbourn CC, Kettle AJ, Hampton MB., Annu. Rev. Biochem. 85(), 2016
PMID: 27050287


Markieren/ Markierung löschen
Markierte Publikationen

Open Data PUB

Web of Science

Dieser Datensatz im Web of Science®


PMID: 30619128
PubMed | Europe PMC

Suchen in

Google Scholar