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Jacob E Choby, Laura A Mike, Ameya A Mashruwala, Brendan F Dutter, Paul M Dunman, Gary A Sulikowski, Jeffrey M Boyd, Eric P Skaar
The rising problem of antimicrobial resistance in Staphylococcus aureus necessitates the discovery of novel therapeutic targets for small-molecule intervention. A major obstacle of drug discovery is identifying the target of molecules selected from high-throughput phenotypic assays. Here, we show that the toxicity of a small molecule termed '882 is dependent on the constitutive activity of the S. aureus virulence regulator SaeRS, uncovering a link between virulence factor production and energy generation. A series of genetic, physiological, and biochemical analyses reveal that '882 inhibits iron-sulfur (Fe-S) cluster assembly most likely through inhibition of the Suf complex, which synthesizes Fe-S clusters...
October 19, 2016: Cell Chemical Biology
Tyler K Nygaard, Scott D Kobayashi, Brett Freedman, Adeline R Porter, Jovanka M Voyich, Michael Otto, Olaf Schneewind, Frank R DeLeo
Staphylococcus aureus is a leading cause of human infections worldwide. The pathogen produces numerous molecules that can interfere with recognition and binding by host innate immune cells, an initial step required for the ingestion and subsequent destruction of microbes by phagocytes. To better understand the interaction of this pathogen with human immune cells, we compared the association of S. aureus and S. epidermidis with leukocytes in human blood. We found that a significantly greater proportion of B cells associated with S...
2016: PloS One
Saer Samanipour, Katherine Langford, Malcolm J Reid, Kevin V Thomas
Gas chromatography coupled with high resolution time of flight mass spectrometry (GC-HR-TOFMS) has gained popularity for the target and suspect analysis of complex samples. However, confident detection of target/suspect analytes in complex samples, such as produced water, remains a challenging task. Here we report on the development and validation of a two stage algorithm for the confident target and suspect analysis of produced water extracts. We performed both target and suspect analysis for 48 standards, which were a mixture of 28 aliphatic hydrocarbons and 20 alkylated phenols, in 3 produced water extracts...
September 9, 2016: Journal of Chromatography. A
Jinxin Zhao, Soon-Ee Cheah, Kade D Roberts, Roger L Nation, Philip E Thompson, Tony Velkov, Zongjun Du, Matthew D Johnson, Jian Li
Polymyxin B and colistin are exclusively active against Gram-negative pathogens and have been used in the clinic as a last-line therapy. In this study, we investigated the antimicrobial activity of a novel polymyxin, FADDI-019, against Staphylococcus aureus. MIC and time-kill assays were employed to measure the activity of FADDI-019 against S. aureus ATCC 700699. Cell morphology was examined with scanning electron microscopy (SEM), and cell membrane polarity was measured using flow cytometry. Transcriptome changes caused by FADDI-019 treatment were investigated using transcriptome sequencing (RNA-Seq)...
July 2016: MSphere
Miren L Baroja, Christine A Herfst, Katherine J Kasper, Stacey X Xu, Daniel A Gillett, Jingru Li, Gregor Reid, John K McCormick
UNLABELLED: Toxic shock syndrome toxin 1 (TSST-1) is a Staphylococcus aureus superantigen that has been implicated in both menstrual and nonmenstrual toxic shock syndrome (TSS). Despite the important role of TSST-1 in severe human disease, a comprehensive understanding of staphylococcal regulatory factors that control TSST-1 expression remains incomplete. The S. aureus exotoxin expression (Sae) operon contains a well-characterized two-component system that regulates a number of important exotoxins in S...
October 1, 2016: Journal of Bacteriology
Nicola J Smyllie, Violetta Pilorz, James Boyd, Qing-Jun Meng, Ben Saer, Johanna E Chesham, Elizabeth S Maywood, Toke P Krogager, David G Spiller, Raymond Boot-Handford, Michael R H White, Michael H Hastings, Andrew S I Loudon
Transcriptional-translational feedback loops (TTFLs) are a conserved molecular motif of circadian clocks. The principal clock in mammals is the suprachiasmatic nucleus (SCN) of the hypothalamus. In SCN neurons, auto-regulatory feedback on core clock genes Period (Per) and Cryptochrome (Cry) following nuclear entry of their protein products is the basis of circadian oscillation [1, 2]. In Drosophila clock neurons, the movement of dPer into the nucleus is subject to a circadian gate that generates a delay in the TTFL, and this delay is thought to be critical for oscillation [3, 4]...
July 25, 2016: Current Biology: CB
Gregory S Orf, Rafael G Saer, Dariusz M Niedzwiedzki, Hao Zhang, Chelsea L McIntosh, Jason W Schultz, Liviu M Mirica, Robert E Blankenship
Light-harvesting antenna complexes not only aid in the capture of solar energy for photosynthesis, but regulate the quantity of transferred energy as well. Light-harvesting regulation is important for protecting reaction center complexes from overexcitation, generation of reactive oxygen species, and metabolic overload. Usually, this regulation is controlled by the association of light-harvesting antennas with accessory quenchers such as carotenoids. One antenna complex, the Fenna-Matthews-Olson (FMO) antenna protein from green sulfur bacteria, completely lacks carotenoids and other known accessory quenchers...
August 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
Fermin E Guerra, Conrad B Addison, Nienke W M de Jong, Joseph Azzolino, Kyler B Pallister, Jos A G van Strijp, Jovanka M Voyich
Neutrophils are the first line of defense after a pathogen has breached the epithelial barriers, and unimpaired neutrophil functions are essential to clear infections. Staphylococcus aureus is a prevalent human pathogen that is able to withstand neutrophil killing, yet the mechanisms used by S. aureus to inhibit neutrophil clearance remain incompletely defined. The production of reactive oxygen species (ROS) is a vital neutrophil antimicrobial mechanism. Herein, we test the hypothesis that S. aureus uses the SaeR/S two-component gene regulatory system to produce virulence factors that reduce neutrophil ROS production...
June 22, 2016: Journal of Leukocyte Biology
Tzu-Ping Ko, Cheng-Yang Huang, Tung-Ju Hsieh, Sheng-Chia Chen, Yu-Ren Chen, Chia-Shin Yang, Hao-Cheng Kuo, Wen-Lung Wang, Tzu-Hung Hsiao, Ching-Heng Lin, Yeh Chen
Two-component system SaeRS of Staphylococcus regulates virulence factor expression through phosphorylation of the DNA-binding regulator SaeR by the sensor histidine kinase SaeS. Here crystal structures of the DNA-binding domain (DBD) of SaeR from two Staphylococcal species Staphylococcus epidermidis and Staphylococcus aureus were determined and showed similar folds. Analyzing the DNA binding activity of three mutants of SeSaeR, we observed that Thr217 is important in binding to the phosphate group of DNA and Trp219 may interact with the base pairs...
June 10, 2016: Biochemical and Biophysical Research Communications
Rafael Saer, Gregory S Orf, Xun Lu, Hao Zhang, Matthew J Cuneo, Dean A A Myles, Robert E Blankenship
The Fenna-Matthews-Olson (FMO) pigment-protein complex in green sulfur bacteria transfers excitation energy from the chlorosome antenna complex to the reaction center. In understanding energy transfer in the FMO protein, the individual contributions of the bacteriochlorophyll pigments to the FMO complex's absorption spectrum could provide detailed information with which molecular and energetic models can be constructed. The absorption properties of the pigments, however, are such that their spectra overlap significantly...
September 2016: Biochimica et Biophysica Acta
Qiang Lou, Yuanfang Ma, Di Qu
Staphylococcus epidermidis, which is a causative pathogen of nosocomial infection, expresses its virulent traits such as biofilm and autolysis regulated by two-component signal transduction system SaeRS. In this study, the S. epidermidis SaeRS was identified to negatively regulate the expression of genes involved in competence (comF, murF), cytolysis (lrgA), and autolysis (lytS) by DNA microarray or real-time RT-PCR analysis. In addition, saeRS mutant showed increased competence and higher susceptibility to antibiotics such as penicillin and oxacillin than the wild-type strain...
April 2016: Journal of Basic Microbiology
Zachary R Tranchemontagne, Ryan B Camire, Vanessa J O'Donnell, Jessfor Baugh, Kristin M Burkholder
Methicillin-resistant Staphylococcus aureus (MRSA) causes invasive, drug-resistant skin and soft tissue infections. Reports that S. aureus bacteria survive inside macrophages suggest that the intramacrophage environment may be a niche for persistent infection; however, mechanisms by which the bacteria might evade macrophage phagosomal defenses are unclear. We examined the fate of the S. aureus-containing phagosome in THP-1 macrophages by evaluating bacterial intracellular survival and phagosomal acidification and maturation and by testing the impact of phagosomal conditions on bacterial viability...
January 2016: Infection and Immunity
Xiaojiao Fan, Xu Zhang, Yuwei Zhu, Liwen Niu, Maikun Teng, Baolin Sun, Xu Li
The SaeR/S two-component regulatory system is essential for controlling the expression of many virulence factors in Staphylococcus aureus. SaeR, a member of the OmpR/PhoB family, is a response regulator with an N-terminal regulatory domain and a C-terminal DNA-binding domain. In order to elucidate how SaeR binds to the promoter regions of target genes, the crystal structure of the DNA-binding domain of SaeR (SaeR(DBD)) was solved at 2.5 Å resolution. The structure reveals that SaeR(DBD) exists as a monomer and has the canonical winged helix-turn-helix module...
August 2015: Acta Crystallographica. Section D, Biological Crystallography
Fan Zhao, Brian L Cheng, Susan Boyle-Vavra, Maria-Luisa Alegre, Robert S Daum, Anita S Chong, Christopher P Montgomery
Recurrent Staphylococcus aureus skin and soft tissue infections (SSTIs) are common despite detectable antibody responses, leading to the belief that the immune response elicited by these infections is not protective. We recently reported that S. aureus USA300 SSTI elicits antibodies that protect against recurrent SSTI in BALB/c but not C57BL/6 mice, and in this study, we aimed to uncover the specificity of the protective antibodies. Using a proteomic approach, we found that S. aureus SSTI elicited broad polyclonal antibody responses in both BALB/c and C57BL/6 mice and identified 10 S...
September 2015: Infection and Immunity
Hoonsik Cho, Do-Won Jeong, Qian Liu, Won-Sik Yeo, Thomas Vogl, Eric P Skaar, Walter J Chazin, Taeok Bae
Calprotectin, the most abundant cytoplasmic protein in neutrophils, suppresses the growth of Staphylococcus aureus by sequestering the nutrient metal ions Zn and Mn. Here we show that calprotectin can also enhance the activity of the SaeRS two component system (TCS), a signaling system essential for production of over 20 virulence factors in S. aureus. The activity of the SaeRS TCS is repressed by certain divalent ions found in blood or neutrophil granules; however, the Zn bound-form of calprotectin relieves this repression...
July 2015: PLoS Pathogens
Thamir M Alshammari, Wa'ad H Al-Kathiri, Hervé Le Louet, Hisham S Aljadhey
OBJECTIVES: To assess completeness of reports in the Saudi Adverse Event Reporting System (SAERS), which is a part of the Saudi Food and Drug Authority pharmacovigilance system for monitoring the safety of medications. METHODS: A cross-sectional study was conducted in Riyadh, Saudi Arabia using the reports that were received between December 2009 and June 2012 in the SAERS. The completeness was assessed by reviewing the components of the adverse drug reactions (ADRs) form, and how many fields were completed...
July 2015: Saudi Medical Journal
David Cue, Jennifer M Junecko, Mei G Lei, Jon S Blevins, Mark S Smeltzer, Chia Y Lee
The SaeRS two-component regulatory system of Staphylococcus aureus is known to affect the expression of many genes. The SaeS protein is the histidine kinase responsible for phosphorylation of the response regulator SaeR. In S. aureus Newman, the sae system is constitutively expressed due to a point mutation in saeS, relative to other S. aureus strains, which results in substitution of proline for leucine at amino acid 18. Strain Newman is unable to form a robust biofilm and we report here that the biofilm-deficient phenotype is due to the saeSP allele...
2015: PloS One
Qiang Lou, Yao-hui Wang, Yuan-fang Ma
OBJECTIVE: To investigate the survival ability of Staphylococcus epidermidis (S. epidermidis) wildtype (WT), saeRS mutant (SAE) and saeRS complementary (SAEC) strains under different concentrations of glucose. METHODS: We measured the survival ability, biofilm forming ability, medium acidity and antimicrobial susceptibility of S. epidermidis in medium containing different concentrations of glucose. RESULTS: Compared with WT, the survival ability, biofilm forming ability and resistance to antibiotics (such as penicillin, oxacillin, gentamicin, ciprofloxacin and amikacin) of saeRS mutant increased significantly in response to glucose...
January 2015: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
Junshu Yang, Xudong Liang, Yinduo Ji
The two-component regulatory system, SaeRS, controls expression of important virulence factors, including toxins and invasins, which contribute to the pathogenicity of Staphylococcus aureus. Previously, we conducted a transcriptomics study for identification of SaeRS regulon and found that inactivation of SaeRS dramatically enhances the transcription of a novel transcriptional regulator (SA1804). This led us to question whether SA1804 is involved in bacterial pathogenicity by regulating the expression of virulence factors...
2015: Frontiers in Microbiology
Oliwia W Zurek, Kyler B Pallister, Jovanka M Voyich
While Staphylococcus aureus accelerates human neutrophil cell death, the underlying host- and pathogen-derived mechanisms remain incompletely defined. Previous studies demonstrated that the S. aureus SaeR/S sensory system is essential for pathogen survival following neutrophil phagocytosis. Herein, we demonstrate that the SaeR/S system promoted accelerated cell death, suppressed phosphorylation of nuclear factor-κB, and reduced interleukin-8 (IL-8) production in human neutrophils. Treatment of neutrophils with recombinant IL-8 significantly reduced bacterial burden and apoptosis...
September 15, 2015: Journal of Infectious Diseases
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