Imperial College London

ProfessorAngelikaGrundling

Faculty of MedicineDepartment of Medicine

Professor of Molecular Microbiology
 
 
 
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Contact

 

+44 (0)20 7594 5256a.grundling Website

 
 
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Location

 

3.21Flowers buildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

46 results found

Baek KT, Bowman L, Millership C, Sogaard MD, Kaever V, Siljamaki P, Savijoki K, Varmanen P, Nyman TA, Grundling A, Frees Det al., 2016, The Cell Wall Polymer Lipoteichoic Acid Becomes Nonessential in Staphylococcus aureus Cells Lacking the ClpX Chaperone, MBIO, Vol: 7, ISSN: 2150-7511

JOURNAL ARTICLE

Bowman L, Zeden MS, Schuster CF, Kaever V, Grundling Aet al., 2016, New Insights into the Cyclic di-Adenosine Monophosphate (c-di-AMP) Degradation Pathway and the Requirement of the Cyclic-Dinucleotide for Acid Stress Resistance in Staphylococcus aureus., Journal of Biological Chemistry, Vol: 291, Pages: 26970-26986, ISSN: 1083-351X

Nucleotide signaling networks are key to facilitate alterations in gene expression, protein function and enzyme activity in response to diverse stimuli. Cyclic di-adenosine monophosphate (c-di-AMP) is an important secondary messenger molecule produced by the human pathogen Staphylococcus aureus and is involved in regulating a number of physiological processes including potassium transport. S. aureus must ensure tight control over its cellular levels as both high levels of the dinucleotide and its absence result in a number of detrimental phenotypes. Here we show that in addition to the membrane bound Asp-His-His and Asp-His-His associated (DHH/DHHA1) domain-containing phosphodiesterase (PDE) GdpP, S. aureus produces a second cytoplasmic DHH/DHHA1 PDE Pde2. Although capable of hydrolyzing c-di-AMP, Pde2 preferentially converts linear 5-phosphadenylyl-adenosine (pApA) to AMP. Using a pde2 mutant strain, pApA was detected for the first time in S. aureus, leading us to speculate that this dinucleotide may have a regulatory role under certain conditions. Moreover, pApA is involved in a feedback inhibition loop that limits GdpP-dependent c-di-AMP hydrolysis. Another protein linked to the regulation of c-di-AMP levels in bacteria is the predicted regulator protein YbbR. Here, it is shown that a ybbR mutant S. aureus strain has increased acid sensitivity that can be bypassed by the acquisition of mutations in a number of genes, including the gene coding for the diadenylate cyclase DacA. We further show that c-di-AMP levels are slightly elevated in the ybbR suppressor strains tested as compared to the wild-type strain. With this, we not only identified a new role for YbbR in acid stress resistance in S. aureus, but also provide further insight into how c-di-AMP levels impact acid tolerance in this organism.

JOURNAL ARTICLE

Corrigan RM, Bellows LE, Wood A, Gruendling Aet al., 2016, ppGpp negatively impacts ribosome assembly affecting growth and antimicrobial tolerance in Gram-positive bacteria, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 113, Pages: E1710-E1719, ISSN: 0027-8424

JOURNAL ARTICLE

Grundling A, Lee VT, 2016, Old concepts, new molecules and current approaches applied to the bacterial nucleotide signalling field, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 371, ISSN: 0962-8436

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Hengge R, Gruendling A, Jenal U, Ryan R, Yildiz Fet al., 2016, Bacterial Signal Transduction by Cyclic Di-GMP and Other Nucleotide Second Messengers, JOURNAL OF BACTERIOLOGY, Vol: 198, Pages: 15-26, ISSN: 0021-9193

JOURNAL ARTICLE

Schuster C, Bellows L, Tosi T, Campeotto, Corrigan, Freemont P, Grundling Aet al., 2016, The second messenger c-di-AMP inhibits the osmolyte uptake system OpuC in Staphylococcus aureus, Science Signaling, Vol: 9, Pages: ra81-ra81, ISSN: 1945-0877

Staphylococcus aureus is an important opportunistic human pathogen that is highly resistant to osmotic stresses. To survive an increase in osmolarity, bacteria immediately take up potassium ions and small organic compounds known as compatible solutes. The second messenger cyclic diadenosine monophosphate (c-di-AMP) reduces the ability of bacteria to withstand osmotic stress by binding to and inhibiting several proteins that promote potassium uptake. We identified OpuCA, the adenosine triphosphatase (ATPase) component of an uptake system for the compatible solute carnitine, as a c-di-AMP target protein in S. aureus and found that the LAC*ΔgdpP strain of S. aureus, which overproduces c-di-AMP, showed reduced carnitine uptake. The paired cystathionine-β-synthase (CBS) domains of OpuCA bound to c-di-AMP, and a crystal structure revealed a putative binding pocket for c-di-AMP in the cleft between the two CBS domains. Thus, c-di-AMP inhibits osmoprotection through multiple mechanisms.

JOURNAL ARTICLE

Zhang Y, Agrebi R, Bellows LE, Collet JF, Kaever V, Gründling Aet al., 2016, Evolutionary adaptation of the essential tRNA methyltransferase TrmD to the signaling molecule 3,5-cAMP in bacteria., Journal of Biological Chemistry, Vol: 292, Pages: 313-327, ISSN: 1083-351X

The nucleotide signaling molecule 3',5'-cyclic adenosine monophosphate (3',5'-cAMP) plays important physiological roles, ranging from carbon catabolite repression in bacteria to mediating the action of hormones in higher eukaryotes, including human. However, it remains unclear whether 3',5'-cAMP is universally present in the Firmicutes group of bacteria. We hypothesized that searching for proteins that bind 3',5'-cAMP might provide new insight into this question. Accordingly, we performed a genome-wide screen, and identified the essential Staphylococcus aureus tRNA m1G37 methyltransferase enzyme TrmD, which is conserved in all three domains of life, as a tight 3',5'-cAMP binding protein. TrmD enzymes are known to use S-adenosyl-L-methionine (AdoMet) as substrate; we shown that 3',5'-cAMP binds competitively with AdoMet to the S. aureus TrmD protein, indicating an overlapping binding site. However, the physiological relevance of this discovery remained unclear, as we were unable to identify a functional adenylate cyclase in S. aureus and only detected 2',3'-cAMP but not 3',5'-cAMP in cellular extracts. Interestingly, TrmD proteins from Escherichia coli and Mycobacterium tuberculosis, organisms known to synthesize 3',5'-cAMP, did not bind this signaling nucleotide. Comparative bioinformatics, mutagenesis and biochemical analyses revealed that the highly conserved Tyr86 residue in E. coli TrmD is essential to discriminate between 3',5'-cAMP and the native substrate AdoMet. Combined with a phylogenetic analysis, these results suggest that amino acids in the substrate binding pocket of TrmD underwent an adaptive evolution to accommodate the emergence of adenylate cyclases and thus the signaling molecule 3',5'-cAMP. Altogether this further indicates that S. aureus does not produce 3',5'-cAMP, which would otherwise competitively inhibit an essential enzyme.

JOURNAL ARTICLE

Campeotto I, Zhang Y, Mladenov MG, Freemont PS, Grundling Aet al., 2015, Complex Structure and Biochemical Characterization of the Staphylococcus aureus Cyclic Diadenylate Monophosphate (c-di-AMP)-binding Protein PstA, the Founding Member of a New Signal Transduction Protein Family, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 290, Pages: 2888-2901, ISSN: 0021-9258

JOURNAL ARTICLE

Corrigan RM, Bowman L, Willis AR, Kaever V, Gruendling Aet al., 2015, Cross-talk between Two Nucleotide-signaling Pathways in Staphylococcus aureus, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 290, Pages: 5826-5839, ISSN: 0021-9258

JOURNAL ARTICLE

Gross CA, Gruendling A, 2015, Editorial overview: Cell regulation: When you think you know it all, there is another layer to be discovered, CURRENT OPINION IN MICROBIOLOGY, Vol: 24, Pages: V-VII, ISSN: 1369-5274

JOURNAL ARTICLE

Moscoso JA, Schramke H, Zhang Y, Tosi T, Dehbi A, Jung K, Gründling Aet al., 2015, Binding of cyclic Di-AMP to the staphylococcus aureus sensor kinase KdpD occurs via the universal stress protein domain and downregulates the expression of the Kdp potassium transporter, Journal of Bacteriology, ISSN: 1098-5530

Nucleotide signalling molecules are important intracellular messengers that regulate a wide range of biological functions. The human pathogen Staphylococcus aureus produces the signalling nucleotide cyclic di-adenosine monophosphate (c-di-AMP). This molecule is common among Gram-positive bacteria and in many organisms essential for survival under standard laboratory growth conditions. In this study, we investigated the interaction of c-di-AMP with the S. aureus KdpD protein. The sensor kinase KdpD forms a two-component signalling system with the response regulator KdpE and regulates the expression of the kdpDE genes and the kdpFABC operon coding for the Kdp potassium transporter components. Here, we show that the S. aureus KdpD protein binds c-di-AMP specifically and with an affinity in the micromolar range through its universal stress protein (USP) domain. This domain is located within the N-terminal cytoplasmic region of KdpD and amino acids of a conserved SxS-X20-FTAxY motif are important for this binding. We further show that KdpD2, a second KdpD protein found in some S. aureus strains, also binds c-di-AMP and our bioinformatics analysis indicates that a subclass of KdpD proteins in c-di-AMP-producing bacteria has evolved to bind this signalling nucleotide. Finally, we show that c-di-AMP binding to KdpD inhibits the up-regulation of the kdpFABC operon under salt stress, thus indicating that c-di-AMP is a negative regulator of potassium uptake in S. aureus. IMPORTANCE: Staphylococcus aureus is an important human pathogen and major cause of food poisoning in western countries. A common method for food preservation is the use of salt to drive dehydration. This study sheds light on the regulation of potassium uptake in Staphylococcus aureus, an important aspect of this bacterium's ability to tolerate high levels of salt. We show that the signalling nucleotide c-di-AMP binds to a regulatory component of the Kdp potassium uptake system and that this binding has an inh

JOURNAL ARTICLE

Baek KT, Grundling A, Mogensen RG, Thogersen L, Petersen A, Paulander W, Frees Det al., 2014, beta-Lactam Resistance in Methicillin-Resistant Staphylococcus aureus USA300 Is Increased by Inactivation of the ClpXP Protease, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 58, Pages: 4593-4603, ISSN: 0066-4804

JOURNAL ARTICLE

Campeotto I, Percy MG, MacDonald JT, Foerster A, Freemont PS, Gruendling Aet al., 2014, Structural and Mechanistic Insight into the Listeria monocytogenes Two-enzyme Lipoteichoic Acid Synthesis System, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 289, Pages: 28054-28069, ISSN: 0021-9258

JOURNAL ARTICLE

Gründling A, 2014, Milestones in nucleotide signaling research: Nucleotide signals are found in bacteria as well as eukaryotes, and may act intra- or extracellularly, Microbe, Vol: 9, Pages: 315-320, ISSN: 1558-7452

JOURNAL ARTICLE

Percy MG, Gruendling A, 2014, Lipoteichoic Acid Synthesis and Function in Gram-Positive Bacteria, ANNUAL REVIEW OF MICROBIOLOGY, VOL 68, Vol: 68, Pages: 81-100, ISSN: 0066-4227

JOURNAL ARTICLE

Reichmann NT, Cassona CP, Monteiro JM, Bottomley AL, Corrigan RM, Foster SJ, Pinho MG, Gruendling Aet al., 2014, Differential localization of LTA synthesis proteins and their interaction with the cell division machinery in Staphylococcus aureus, MOLECULAR MICROBIOLOGY, Vol: 92, Pages: 273-286, ISSN: 0950-382X

JOURNAL ARTICLE

Corrigan RM, Campeotto I, Jeganathan T, Roelofs KG, Lee VT, Gruendling Aet al., 2013, Systematic identification of conserved bacterial c-di-AMP receptor proteins, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 9084-9089, ISSN: 0027-8424

JOURNAL ARTICLE

Corrigan RM, Gruendling A, 2013, Cyclic di-AMP: another second messenger enters the fray, NATURE REVIEWS MICROBIOLOGY, Vol: 11, Pages: 513-524, ISSN: 1740-1526

JOURNAL ARTICLE

Gruendling A, 2013, Potassium Uptake Systems in Staphylococcus aureus: New Stories about Ancient Systems, MBIO, Vol: 4, ISSN: 2150-7511

JOURNAL ARTICLE

Mercedes Palomino M, Allievi MC, Gruendling A, Sanchez-Rivas C, Ruzal SMet al., 2013, Osmotic stress adaptation in Lactobacillus casei BL23 leads to structural changes in the cell wall polymer lipoteichoic acid, MICROBIOLOGY-SGM, Vol: 159, Pages: 2416-2426, ISSN: 1350-0872

JOURNAL ARTICLE

Reichmann NT, Cassona CP, Gruendling A, 2013, Revised mechanism of D-alanine incorporation into cell wall polymers in Gram-positive bacteria, MICROBIOLOGY-SGM, Vol: 159, Pages: 1868-1877, ISSN: 1350-0872

JOURNAL ARTICLE

Meredith TC, Wang H, Beaulieu P, Gründling A, Roemer Tet al., 2012, Harnessing the power of transposon mutagenesis for antibacterial target identification and evaluation., Mob Genet Elements, Vol: 2, Pages: 171-178, ISSN: 2159-2543

Determining the mechanism of action of bacterial growth inhibitors can be a formidable challenge in the progression of small molecules into antibacterial therapies. To help address this bottleneck, we have developed a robust transposon mutagenesis system using a suite of outward facing promoters in order to generate a comprehensive range of expression genotypes in Staphylococcus aureus from which to select defined compound-resistant transposon insertion mutants. Resistance stemming from either gene or operon over/under-expression, in addition to deletion, provides insight into multiple factors that contribute to a compound's observed activity, including means of cell envelope penetration and susceptibility to efflux. By profiling the entire resistome, the suitability of an antibacterial target itself is also evaluated, sometimes with unanticipated results. We herein show that for the staphylococcal signal peptidase (SpsB) inhibitors, modulating expression of lipoteichoic acid synthase (LtaS) confers up to a 100-fold increase in the minimal inhibitory concentration. As similarly efficient transposition systems are or will become established in other bacteria and cell types, we discuss the utility, limitations and future promise of Tnp mutagenesis for determining both a compound's mechanism of action and in the evaluation of novel targets.

JOURNAL ARTICLE

Smith EJ, Corrigan RM, van der Sluis T, Gruendling A, Speziale P, Geoghegan JA, Foster TJet al., 2012, The immune evasion protein Sbi of Staphylococcus aureus occurs both extracellularly and anchored to the cell envelope by binding lipoteichoic acid, MOLECULAR MICROBIOLOGY, Vol: 83, Pages: 789-804, ISSN: 0950-382X

JOURNAL ARTICLE

Smith EJ, Corrigan RM, van der Sluis T, Gründling A, Speziale P, Geoghegan JA, Foster TJet al., 2012, The immune evasion protein Sbi of Staphylococcus aureus occurs both extracellularly and anchored to the cell envelope by binding lipoteichoic acid., Mol Microbiol

The Sbi protein of Staphylococcus aureus comprises two IgG binding domains similar to those of protein A and a region that triggers the activation of complement C3. Sbi is expressed on the cell surface but its C-terminal domain lacks motifs associated with wall or membrane anchoring of proteins in Gram-positive bacteria. Cell-associated Sbi fractionates with the cytoplasmic membrane and is not solubilised during protoplast formation. S.aureus expressing Sbi truncates of the C-terminal Y domain allowed identification of residues that are required for association of Sbi with the membrane. Recombinant Sbi bound to purified cytoplasmic membrane material in vitro and to purified lipoteichoic acid. This explains how Sbi partitions with the membrane in fractionation experiments yet is partially exposed on the cell surface. An LTA-defective mutant of S. aureus had reduced levels of Sbi in the cytoplasmic membrane.

JOURNAL ARTICLE

Corrigan RM, Abbott JC, Burhenne H, Kaever V, Gruendling Aet al., 2011, c-di-AMP Is a New Second Messenger in Staphylococcus aureus with a Role in Controlling Cell Size and Envelope Stress, PLOS PATHOGENS, Vol: 7, ISSN: 1553-7366

JOURNAL ARTICLE

Reichmann NT, Gruendling A, 2011, Location, synthesis and function of glycolipids and polyglycerolphosphate lipoteichoic acid in Gram-positive bacteria of the phylum Firmicutes, FEMS MICROBIOLOGY LETTERS, Vol: 319, Pages: 97-105, ISSN: 0378-1097

JOURNAL ARTICLE

Woermann ME, Corrigan RM, Simpson PJ, Matthews SJ, Gruendling Aet al., 2011, Enzymatic activities and functional interdependencies of Bacillus subtilis lipoteichoic acid synthesis enzymes, MOLECULAR MICROBIOLOGY, Vol: 79, Pages: 566-583, ISSN: 0950-382X

JOURNAL ARTICLE

Woermann ME, Reichmann NT, Malone CL, Horswill AR, Gruendling Aet al., 2011, Proteolytic Cleavage Inactivates the Staphylococcus aureus Lipoteichoic Acid Synthase, JOURNAL OF BACTERIOLOGY, Vol: 193, Pages: 5279-5291, ISSN: 0021-9193

JOURNAL ARTICLE

Xia G, Corrigan RM, Winstel V, Goerke C, Gruendling A, Peschel Aet al., 2011, Wall Teichoic Acid-Dependent Adsorption of Staphylococcal Siphovirus and Myovirus, JOURNAL OF BACTERIOLOGY, Vol: 193, Pages: 4006-4009, ISSN: 0021-9193

JOURNAL ARTICLE

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