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365 results on '"Shaw, Lindsey N."'

2. Heteroaryl Phosphonates as Noncovalent Inhibitors of Both Serine- and Metallocarbapenemases

Author

Pemberton, Orville A, Jaishankar, Priyadarshini, Akhtar, Afroza, Adams, Jessie L, Shaw, Lindsey N, Renslo, Adam R, and Chen, Yu

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Emerging Infectious Diseases, Antimicrobial Resistance, Prevention, Biodefense, Vaccine Related, Infectious Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Anti-Bacterial Agents, Bacterial Proteins, Crystallography, X-Ray, Drug Design, Enterobacter cloacae, Escherichia coli, HEK293 Cells, Humans, Imipenem, Klebsiella pneumoniae, Ligands, Microsomes, Liver, Molecular Conformation, Organophosphonates, Pseudomonas aeruginosa, beta-Lactamase Inhibitors, beta-Lactamases, beta-Lactams, Medicinal and Biomolecular Chemistry, Organic Chemistry, Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, Pharmacology and pharmaceutical sciences, Medicinal and biomolecular chemistry, Organic chemistry
Abstract

Gram-negative pathogens expressing serine β-lactamases (SBLs) and metallo-β-lactamases (MBLs), especially those with carbapenemase activity, threaten the clinical utility of almost all β-lactam antibiotics. Here we describe the discovery of a heteroaryl phosphonate scaffold that exhibits noncovalent cross-class inhibition of representative carbapenemases, specifically the SBL KPC-2 and the MBLs NDM-1 and VIM-2. The most potent lead, compound 16, exhibited low nM to low μM inhibition of KPC-2, NDM-1, and VIM-2. Compound 16 potentiated imipenem efficacy against resistant clinical and laboratory bacterial strains expressing carbapenemases while showing some cytotoxicity toward human HEK293T cells only at concentrations above 100 μg/mL. Complex structures with KPC-2, NDM-1, and VIM-2 demonstrate how these inhibitors achieve high binding affinity to both enzyme classes. These findings provide a structurally and mechanistically new scaffold for drug discovery targeting multidrug resistant Gram-negative pathogens and more generally highlight the active site features of carbapenemases that can be leveraged for lead discovery.

Published
2019

3. Steroid Drugs Inhibit Bacterial Respiratory Oxidases and Are Lethal Toward Methicillin-Resistant Staphylococcus aureus

Author

Henry, Samantha A, primary, Webster, Calum M, additional, Shaw, Lindsey N, additional, Torres, Nathanial J, additional, Jobson, Mary-Elizabeth, additional, Totzke, Brendan C, additional, Jackson, Jessica K, additional, McGreig, Jake E, additional, Wass, Mark N, additional, Robinson, Gary K, additional, and Shepherd, Mark, additional

Published
2024
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4. Antibacterial Spectrum of a Tetrazole-Based Reversible Inhibitor of Serine β-Lactamases

Author

Pemberton, Orville A, Zhang, Xiujun, Nichols, Derek A, DeFrees, Kyle, Jaishankar, Priyadarshini, Bonnet, Richard, Adams, Jessie, Shaw, Lindsey N, Renslo, Adam R, and Chen, Yu

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Infectious Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Anti-Bacterial Agents, Gram-Negative Bacteria, Microbial Sensitivity Tests, Tetrazoles, beta-Lactamases, antibacterial, inhibitor, β-lactamase, Microbiology, Pharmacology and Pharmaceutical Sciences, Medical microbiology, Pharmacology and pharmaceutical sciences
Abstract

CTX-M is the most prevalent family of extended-spectrum β-lactamases. We recently developed a tetrazole-derived noncovalent inhibitor of CTX-M-9. Here, we present the biochemical and microbiological activity of this inhibitor across a representative panel of serine β-lactamases and Gram-negative bacteria. The compound displayed significant activity against all major subgroups of CTX-M, including CTX-M-15, while it exhibited some low-level inhibition of other serine β-lactamases. Complex crystal structures with the CTX-M-14 S237A mutant and CTX-M-27 illustrate the binding contribution of specific active-site residues on the β3 strand. In vitro pharmacokinetic studies revealed drug-like properties and positive prospects for further optimization. These studies suggest that tetrazole-based compounds can provide novel chemotypes for future serine β-lactamase inhibitor discovery.

Published
2018

12. Staphylococcus aureus SigS Induces Expression of a Regulatory Protein Pair That Modulates Its mRNA Stability

Author

Al Ali, Amer, primary, Alsulami, Jamilah, additional, Aubee, Joseph I., additional, Idowu, Ayotimofe, additional, Tomlinson, Brooke R., additional, Felton, Emily A., additional, Jackson, Jessica K., additional, Kennedy, Sarah J., additional, Torres, Nathanial J., additional, Shaw, Lindsey N., additional, and Thompson, Karl M., additional

Published
2023
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18. Stochastic activation of a family of TetR type transcriptional regulators controls phenotypic heterogeneity in Acinetobacter baumannii

Author

Pérez-Varela, María, primary, Tierney, Aimee R P, additional, Dawson, Emma, additional, Hutcheson, Anna R, additional, Tipton, Kyle A, additional, Anderson, Sarah E, additional, Haldopoulos, Marina E, additional, Song, Shaina, additional, Tomlinson, Brooke R, additional, Shaw, Lindsey N, additional, Weiss, David S, additional, Kim, Minsu, additional, and Rather, Philip N, additional

Published
2022
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24. The novel two-component system AmsSR governs alternative metabolic pathway usage in Acinetobacter baumannii.

Author

Casella, Leila G., Torres, Nathanial J., Tomlinson, Brooke R., Shepherd, Mark, and Shaw, Lindsey N.

Subjects
TRANSMEMBRANE domains, POISONS, CELL membranes, ALTERNATIVE fuels, OXYGEN consumption, HISTIDINE, ACINETOBACTER baumannii
Abstract

In this study, we identify a novel two-component system in Acinetobacter baumannii (herein named AmsSR for regulator of alternative metabolic systems) only present in select gammaproteobacterial and betaproteobacterial species. Bioinformatic analysis revealed that the histidine kinase, AmsS, contains 14 predicted N-terminal transmembrane domains and harbors a hybrid histidine kinase arrangement in its C-terminus. Transcriptional analysis revealed the proton ionophore CCCP selectively induces PamsSR expression. Disruption of amsSR resulted in decreased intracellular pH and increased depolarization of cytoplasmic membranes. Transcriptome profiling revealed a major reordering of metabolic circuits upon amsR disruption, with energy generation pathways typically used by bacteria growing in limited oxygen being favored. Interestingly, we observed enhanced growth rates for mutant strains in the presence of glucose, which led to overproduction of pyruvate. To mitigate the toxic effects of carbon overflow, we noted acetate overproduction in amsSR-null strains, resulting from a hyperactive Pta-AckA pathway. Additionally, due to altered expression of key metabolic genes, amsSR mutants favor an incomplete TCA cycle, relying heavily on an overactive glyoxylate shunt. This metabolic reordering overproduces NADH, which is not oxidized by the ETC; components of which were significantly downregulated upon amsSR disruption. As a result, the mutants almost exclusively rely on substrate phosphorylation for ATP production, and consequently display reduced oxygen consumption in the presence of glucose. Collectively, our data suggests that disruption of amsSR affects the function of the aerobic respiratory chain, impacting the energy status of the cell, which in turn upregulates alternative metabolic and energy generation pathways. [ABSTRACT FROM AUTHOR]

Published
2023
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44. Staphopain B

Author

Kantyka, Tomasz, primary, Shaw, Lindsey N., additional, and Potempa, Jan, additional

Published
2013
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45. Staphopain A

Author

Kantyka, Tomasz, primary, Shaw, Lindsey N., additional, and Potempa, Jan, additional

Published
2013
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46. Contributors

Author

Abbott, Catherine Anne, primary, Abraham, Carmela R., additional, Adachi, Hideki, additional, Adachi, Osao, additional, Adam, Zach, additional, Adams, Michael W.W., additional, Adang, Michael J., additional, Adham, Ibrahim M., additional, Aducci, Patrizia, additional, Agard, David A., additional, Agranovsky, Alexey A., additional, Akamatsu, Tetsuya, additional, Akiyama, Yoshinori, additional, Albrechtsen, Reidar, additional, Alejo, Alí, additional, Amberg, Sean M., additional, Amerik, Alexander Y., additional, Amparyup, Piti, additional, Andrade, Felipe, additional, Andrés, Germán, additional, Andrews, Daniel M., additional, Andrews, Robert K., additional, Antalis, Toni M., additional, Anthony, Colin S., additional, Aoki, Naoya, additional, Apte, Suneel S., additional, Arima, Kazunari, additional, Arlaud, Gérard, additional, Arni, Raghuvir Krishnaswamy, additional, Arnoux, Pascal, additional, Aronson, Nathan N., additional, Arthur, Michel, additional, Asano, Yasuhisa, additional, Ascenzi, Paolo, additional, Assakura, Marina T., additional, Auld, David S., additional, Ávila, Veridiana de Melo Rodrigues, additional, Avilés, Francesc X., additional, Awad, William M., additional, Bachhawat, Anand K., additional, Bai, Shan, additional, Baird, Teaster T., additional, Bajaj, S. Paul, additional, Baker, Susan C., additional, Banbula, Agnieszka, additional, Barrett, Alan J., additional, Barrowman, Jemima, additional, Bartlett, John D., additional, Bartsch, Jörg W., additional, Baschuk, Nikola, additional, Baskova, Isolda P., additional, Batra, Jyotsna, additional, Bauer, Karl, additional, Baumann, Ulrich, additional, Baumeister, Wolfgang, additional, Bauvois, Cédric, additional, Bayés, Alex, additional, Beauvais, Anne, additional, Becker-Pauly, Christoph, additional, Begley, Tadhg P., additional, Békés, Miklós, additional, Belas, Robert, additional, Beleford, Daniah, additional, Beppu, Teruhiko, additional, Bergmann, Ernst M., additional, Bernard, Bruno A., additional, Bernard, Dominique, additional, Berndt, Michael C., additional, Berruti, Giovanna, additional, Berry, Colin, additional, Bertenshaw, Greg P., additional, Betzel, Christian, additional, Bhaskarla, Chetana, additional, Bhosale, Manoj, additional, Bierbaum, Gabriele, additional, Bjarnason Jón, B., additional, Blaber, Michael, additional, Blackman, Michael J., additional, Blinkovsky, Alexander, additional, Boeke, Jef D., additional, Bogyo, Matthew, additional, Bohn, Stefan, additional, Boileau, Guy, additional, Boland, Mike, additional, Bolken, Tové C., additional, Bond, Judith S., additional, Bondeson, Jan, additional, Bordallo, Javier, additional, Borelli, Claudia, additional, Botelho, Tiago O., additional, Bott, Richard R., additional, Bourne, David G., additional, Bovenschen, Niels, additional, Bradshaw, Ralph A., additional, Breddam, Klaus, additional, Brew, Keith, additional, Brindley, Paul J., additional, Brinkman, Diane L., additional, Britton, Collette, additional, Broadbent, Jeff R., additional, Broadhurst, Anne, additional, Brómme, Dieter, additional, Broom, Murray, additional, Brown, Jeremy S., additional, Brown, Mark A., additional, Bruchhaus, Iris, additional, Burleigh, Barbara A., additional, Burns, Kristin E., additional, Burrows, James F., additional, Butler, Michael J., additional, Buttle, David J., additional, Byrd, Chelsea M., additional, Byun, Tony, additional, Cadel, Sandrine, additional, Caffrey, Conor R., additional, Cal, Santiago, additional, Caldentey, Javier, additional, Candela, Thomas, additional, Capasso, Clemente, additional, Capriogilio, Daniel R., additional, Carginale, Vincenzo, additional, Carmona, Adriana Karaoglanovic, additional, Carruthers, Vern B., additional, Castellino, Francis J., additional, Catanese, Joseph J., additional, Caterson, Bruce, additional, Caughey, George H., additional, Cawley, Naimh X., additional, Cawston, Tim E., additional, Cazzulo, Juan José, additional, Chai, Jijie, additional, Chai, Karl X., additional, Chaim, Olga Meiri, additional, Chang, L.S., additional, Chao, Julie, additional, Chapot-Chartier, Marie-Pierre, additional, Charli, Jean-Louis, additional, Charlier, Paulette, additional, Chave, Karen J., additional, Chen, Jian-Min, additional, Chen, Jinq-May, additional, Chen, Li-Mei, additional, Chen, Ya-Wen, additional, Chen, Yu-Yen, additional, Chevrier, Bernard, additional, Chich, Jean-François, additional, Chien, Jeremy, additional, Chimalapati, Suneeta, additional, Cho, Ki Joon, additional, Choi, Kwan Yong, additional, Chuang, Woei-Jer, additional, Chung, Chin Ha, additional, Chung, Ivy Yeuk Wah, additional, Clamagirand, Christine, additional, Clark, Ian M., additional, Clarke, Adrian K., additional, Clarke, Nicola E., additional, Clarke, Steven Gerard, additional, Clauziat, Philippe, additional, Clements, Judith A., additional, Coffinier, Catherine, additional, Cohen, Paul, additional, Colige, Alain, additional, Collignon, Anne, additional, Colloms, Sean D., additional, Conzelmann, Andreas, additional, Coombs, Graham H., additional, Cooney, Jakki C., additional, Cooper, Jonathan B., additional, Cooper, Max D., additional, Copeland, Nikki A., additional, Cottrell, Graeme S., additional, Coyle, Joseph T., additional, Craik, Charles S., additional, Creemers, John W.M., additional, Cretu, Daniela, additional, Croce, Jenifer, additional, Cross, Keith J., additional, Cueva, Rosario, additional, Cui, Sheng, additional, Cunha, Luis, additional, Cutting, Simon, additional, d’Enfert, Christophe, additional, D’Orchymont, Hugues, additional, Dahlbäck, Björn, additional, Dai, Shujia, additional, Dalbey, Ross E., additional, Dalton, John P., additional, Dando, Pam M., additional, Daniel, R.M., additional, Danilov, Sergei M., additional, Davies, Donna E., additional, De Araujo, Heloisa S., additional, De los Santos, Teresa, additional, de Luca, Viviana, additional, De Meester, Ingrid, additional, de Oliveira, Ana Karina, additional, de Oliveira, Eduardo Brandt, additional, De Oliveira, Pedro Lagerblad, additional, de Vos, Sarah, additional, Declercq, Jeroen, additional, Declercq, Wim, additional, Deghmane, Ala-Eddine, additional, Dekker, Niek, additional, Del Prete, Sonia, additional, Del Rosal, Marina, additional, Delmas, Bernard, additional, DeLotto, Robert, additional, Demidyuk, Ilya V., additional, Denison, Mark R., additional, Deussing, Jan M., additional, Devi, Lakshmi A., additional, Diamandis, Eleftherios P., additional, Diaz, Isabel, additional, Díaz-Perales, Araceli, additional, Dijkstra, Bauke W., additional, Ding, Yan, additional, Dixon, Jack E., additional, Dodt, Johannes, additional, Dokland, Terje, additional, Dolenc, Iztok, additional, Dong, Ningzheng, additional, Dong, Tran Cat, additional, Dong, Ying, additional, Dongre, Mitesh, additional, Donovan, Mark, additional, Dore, Timothy M., additional, Dorstyn, Loretta, additional, Dou, Hong, additional, Dou, Zhicheng, additional, Dougall, Annette M., additional, Drag, Marcin, additional, Dudley, Edward G., additional, Dunn, Ben M., additional, Dupuy, Bruno, additional, Duque-Magalhāes, Maria Conceicāo, additional, Durá, M. Asunción, additional, Eeckhout, Yves, additional, Eijsink, Vincent, additional, Eisen, Arthur Z., additional, Eissa, Azza, additional, Eklund, Sandra, additional, Eletr, Ziad M., additional, Ellis, Vincent, additional, Engel, Wolfgang, additional, Erdös, Ervin G., additional, Escalante, Teresa, additional, Estell, David A., additional, Etscheid, Michael, additional, Evans, Herbert J., additional, Everett, Roger D., additional, Faesen, Alex C., additional, Fahrenholz, Falk, additional, Fanjul-Fernández, Miriam, additional, Farady, Christopher J., additional, Feller, Georges, additional, Feng, Hong, additional, Fenster, Kurt M., additional, Férec, Claude, additional, Ferrari, Silvia, additional, Fingleton, Barbara, additional, Fisher, Jed F., additional, Fives-Taylor, Paula M., additional, Fong, Loren G., additional, Forneris, F., additional, Forster, Brian M., additional, Forster, Friedrich, additional, Foster, Simon J., additional, Foulon, Thierry, additional, Foundling, Stephen I., additional, Fox, Jay William, additional, Franzetti, Bruno, additional, Frasch, Alejandra P., additional, Freeze, Hudson H., additional, Frère, Jean-Marie, additional, Frey, Teryl K., additional, Fricke, Beate, additional, Fricker, Lloyd D., additional, Fridman, Rafael, additional, Froelich, Christopher J., additional, Fröhlich, Camilla, additional, Fu, Hsueh-Liang, additional, Fuhrmann, Cynthia N., additional, Fujimura, Satoshi, additional, Fujiwara, Hiroshi, additional, Fukushima, Jun, additional, Fukuyama, Keiichi, additional, Fuller, Robert S., additional, Fusek, Martin, additional, Gaboriaud, Christine, additional, Gache, Christian, additional, Gakh, Oleksandr, additional, Gal, Peter, additional, Gao, Junjun, additional, García-Sastre, Adolfo, additional, Gardiner, Donald L., additional, Gatehouse, John A., additional, Gaucher, G.M., additional, Gauthier, Francis, additional, Ghuysen, Jean-Marie, additional, Gibson, Wade, additional, Gillies, Jennifer, additional, Glaser, Elzbieta, additional, Glaser, Fabian, additional, Glickman, Michael H., additional, Goettig, Peter, additional, Goffin, Colette, additional, Gohda, Eiichi, additional, Goldberg, Alfred L., additional, Goldberg, Daniel E., additional, Goldberg, Gregory I., additional, Goldfarb, Nathan E., additional, Gomis-Rüth, F. Xavier, additional, Gopal, B., additional, Gorbalenya, Alexander E., additional, Gordon, Stuart G., additional, Gorrell, Mark D., additional, Götz, Friedrich, additional, Goulas, Theodoros, additional, Gouzy-Darmon, Cécile, additional, Govind, K., additional, Gráf, Lászlo, additional, Granados, Robert R., additional, Gräwert, Melissa Ann, additional, Gray, Douglas A., additional, Graycar, Thomas P., additional, Green, Jonathan A., additional, Gremski, Luiza Helena, additional, Groll, Michael, additional, Gromova, Tania Yu, additional, Gros, P., additional, Grubman, Marvin J., additional, Grunden, Amy M., additional, Gudmundsdóttir, Ágústa, additional, Guinand, Micheline, additional, Gully, Djamel, additional, Gustchina, Alla, additional, Gutiérrez, José María, additional, Ha, Byung Hak, additional, Haeggström, Jesper Z., additional, Hageman, James H., additional, Haiko, Johanna, additional, Hailfinger, Stephan, additional, Haitchi, Hans Michael, additional, Han, Ji Seon, additional, Hanquez, Chantal, additional, Harada, Minoru, additional, Hara-Nishimura, Ikuko, additional, Harboe, Marianne, additional, Härd, Torleif, additional, Harris, David A., additional, Hassiepen, Ulrich, additional, Hata, Shoji, additional, Hattori, Akira, additional, He, Rong-Qiao, additional, Heck, Albert J.R., additional, Hendricks, Dirk F., additional, Henrich, Bernhard, additional, Henriet, Patrick, additional, Hernández-Arana, Andrés, additional, Herrera-Camacho, Irma, additional, Heussipp, Gerhard, additional, Hibino, Toshihiko, additional, Hicks, P.M., additional, Hillman, Bradley I., additional, Hiraoka, B. Yukihiro, additional, Hiratake, Jun, additional, Hizukuri, Yohei, additional, Ho, Heng-Chien, additional, Hoa, Ngo Thi, additional, Hochstrasser, Mark, additional, Hodge, Kathryn M., additional, Hofmann, Theo, additional, Hohn, Thomas, additional, Hoidal, John R., additional, Höltje, Joachim-Volker, additional, Homma, Koichi J., additional, Honek, John F., additional, Hook, Vivian Y.H., additional, Hooper, John D., additional, Hooper, Nigel M., additional, Hosoi, Kazuo, additional, Howe, Christopher J., additional, Hruby, Dennis E., additional, Hseih, James J.-D., additional, Hsu, Chun-Chieh, additional, Huang, Tony T., additional, Huang, Tur-Fu, additional, Huet, Yoann, additional, Hughes, Clare, additional, Hugonnet, Jean-Emmanuel, additional, Huston, Adrienne L., additional, Ibrahim-Granet, Oumaïma, additional, Ichishima, Eiji, additional, Ikehara, Yukio, additional, Inagami, Tadashi, additional, Ingram, Jessica, additional, Isaac, R.E., additional, Isaya, Grazia, additional, Isaza, Clara E., additional, Ishii, Shin-ichi, additional, Isnard, Amandine, additional, Ito, Kiyoshi, additional, Ito, Koreaki, additional, Itoh, Yoshifumi, additional, Iturrioz, Xavier, additional, Iwanaga, Sadaaki, additional, Jack, Ralph W., additional, Jackson, Mel C., additional, James, Michael N.G., additional, Janata, Jiří, additional, Janoir, Claire, additional, Janska, Hanna, additional, Jarrell, Ken F., additional, Jaskolski, Mariusz, additional, Jaswal, Sheila S., additional, Jean, Ying Y., additional, Jenne, Dieter E., additional, Jeon, Young Joo, additional, Jiang, Ping, additional, Johnson, John E., additional, Johnson, Michael D., additional, Johnston, James A., additional, Jones, Amanda, additional, Jones, Elizabeth W., additional, Joudiou, Carine, additional, Juliano, Luiz, additional, Jung, Hea-Jin, additional, Jupp, Ray, additional, Kagawa, Todd F., additional, Kalbacher, Hubert, additional, Kamata, Yayoi, additional, Kaminogawa, Shuichi, additional, Kamio, Yoshiyuki, additional, Kaneda, Makoto, additional, Kang, Sung Gyun, additional, Kang, Sung Hwan, additional, Kania, Mary, additional, Kantyka, Tomasz, additional, Kanzawa, Nobuyuki, additional, Karim, Abdulkarim Y., additional, Kasumi, Takafumi, additional, Kataoka, Hiroaki, additional, Kaur, Hardeep, additional, Kawabata, Shun-Ichiro, additional, Kawaguchi, Mari, additional, Kay, John, additional, Kaynar, Murat, additional, Keiler, Kenneth C., additional, Kelly, R.M., additional, Kenton, Nathaniel T., additional, Kerr, Michael A., additional, Kersse, Kristof, additional, Kervinen, Jukka, additional, Kessler, Benedikt M., additional, Kessler, Efrat, additional, Khoronen, Timo K., additional, Kidd, Simon, additional, Kikkert, Marjolein, additional, Kilian, Mogens, additional, Kim, Do-Hyung, additional, Kim, Doyoun, additional, Kim, Eunice EunKyeong, additional, Kim, In Seop, additional, Kim, Jung-Gun, additional, Kim, Kyeong Kyu, additional, Kim, Kyung Hyun, additional, Kimber, Matthew S., additional, Kimura, Yukio, additional, Kirschke, Heidrun, additional, Kiso, Yoshiaki, additional, Kleanthous, Colin, additional, Klein, Jürgen R., additional, Klemba, Michael, additional, Kmiec, Beata, additional, Kobayashi, Hideyuki, additional, Kodama, Hiroyuki, additional, Koelsch, Gerald, additional, Kok, Jan, additional, Kolattukody, P.E., additional, Kolb, Fabrice A., additional, Kolmar, Harald, additional, Komori, Yumiko, additional, Konvalinka, Jan, additional, Korkmaz, Brice, additional, Kostrov, Sergey V., additional, Kräusslich, Hans-Georg, additional, Krczal, Gabi, additional, Kress, Lawrence F., additional, Kristjánsson, Magnüs Már, additional, Kučera, Tomáš, additional, Kukday, Sayali S., additional, Kumagai, Hidehiko, additional, Kumar, Sharad, additional, Kumarasiri, Malika, additional, Kumazaki, Takashi, additional, Kümmerer, Beate M., additional, Kuno, Kouji, additional, Kurkinen, Markku, additional, Kutejová, Eva, additional, Kveiborg, Marie, additional, Kwarciak, Agnieszka, additional, Laakkonen, Liisa, additional, Labrou, Nikolaos E., additional, Laing, Gavin D., additional, Lamppa, Gayle, additional, Langer, Thomas, additional, Laursen, Richard A., additional, Lawrenson, Richard A., additional, Layne, Matthew D., additional, Le Bonniec, Bernard F., additional, Leal, María C., additional, Lechan, Ronald M., additional, Lee, David H., additional, Lee, Irene, additional, Lee, Jae, additional, Lee, Kye Joon, additional, Lee, Soohee, additional, Lei, Xiaobo, additional, Leis, Jonathan, additional, LeMosy, Ellen K., additional, Lepage, Thierry, additional, Leppla, Stephen H., additional, Lesner, Adam, additional, Lessard, Ivan A.D., additional, Lhomond, Guy, additional, Li, Huilin, additional, Li, Shu-Ming, additional, Li, Weiguo, additional, Liao, Ta-Hsiu, additional, Liddington, Robert C., additional, Lieber, Toby, additional, Lijnen, H.R., additional, Lima, Christopher D., additional, Lin, Chen-Yong, additional, Lin, Gang, additional, Lin, Ming T., additional, Lin, Xinli, additional, Lin, Yee-Shin, additional, Lindsay, L.L., additional, Lipscomb, William N., additional, Little, John W., additional, Liu, Ching-Chuan, additional, Liu, Chuan-ju, additional, Lively, Mark O., additional, Livnat-Levanon, Nurit, additional, Ljungdahl, Per O., additional, Llorens-Cortes, Catherine, additional, Lobel, Peter, additional, Loh, Y. Peng, additional, Lohi, Jouko, additional, Lomonossoff, G.P., additional, Looze, Yvan, additional, López-Otin, Carlos, additional, Lopez-Quezada, Landys, additional, Loukas, Alex, additional, Lu, Long-Sheng, additional, Lundwall, Áke, additional, Luo, Liu-Ying, additional, Lupas, Andrei, additional, Luthe, Dawn S., additional, Lynch, Nicholas J., additional, Lyons, Peter J., additional, MacKay, Vivian L., additional, Macleod, Jesica M. Levingston, additional, Magdolen, Viktor, additional, Mainardi, Jean-Luc, additional, Mäkinen, Kauko K., additional, Mallari, Jeremy P., additional, Manandhar, Surya P., additional, Mandelbaum, Fajga R., additional, Manicone, Anne M., additional, Mansfeld, Johanna, additional, Marcotrigiano, Joseph, additional, Mares, Michael, additional, Marfany, Gemma, additional, Markland, Francis S., additional, Marokházi, Judith, additional, Marquis, Hélène, additional, Marr, Robert A., additional, Martegani, Enzo, additional, Martin, Erik W., additional, Martinez, Manuel, additional, Martins, L. Miguel, additional, Maruyama, Masato, additional, Maruyama, Masugi, additional, Maruyama, Sususmu, additional, Masaki, Takeharu, additional, Massoumi, Ramin, additional, Mathew, Rency T., additional, Matrisian, Lynn M., additional, Matsuda, Yoshihiro, additional, Matsushita, Osamu, additional, Matuschek, Marco, additional, Matušková, Anna, additional, Matúz, Krisztina, additional, Mauch, Cornelia, additional, Maurizi, Michael R., additional, Mayr, Lorenz M., additional, McCafferty, Dewey G., additional, McDonald, J. Ken, additional, McKerrow, James H., additional, McMillan, David, additional, Mecham, Robert P., additional, Mehta, Darshini P., additional, Meisinger, Chris, additional, Mellors, Alan, additional, Melton, Roger G., additional, Melvin, Jeffrey A., additional, Ménard, Robert, additional, Menéndez-Arias, Luis, additional, Menezes, Milene C., additional, Mesecar, Andrew, additional, Mesnage, Stéphane, additional, Meyer, Diane H., additional, Meyers, Gregor, additional, Michaelis, Susan, additional, Michalska, Karolina, additional, Mielicki, Wojciech P., additional, Mierau, Igor, additional, Mikoulinskaia, Galina V., additional, Miller, Charles G., additional, Miller, Lydia K., additional, Mills, John, additional, Mills, Kenneth V., additional, Min, Jinrong, additional, Mistou, Michel-Yves, additional, Misumi, Yoshio, additional, Miyoshi, Shin-ichi, additional, Mizutani, Shigehiko, additional, Mobashery, Shahriar, additional, Mochizuki, Satsuki, additional, Mock, William L., additional, Möhrlen, Frank, additional, Moiré, Nathalie, additional, Monahan, Paul E., additional, Moncada-Pazos, Angela, additional, Monnet, Véronique, additional, Monod, Michel, additional, Montecucco, Cesare, additional, Morelli, Laura, additional, Mori, Sumiko, additional, Morita, Takashi, additional, Morrissey, James H., additional, Morse, Richard J., additional, Mort, John S., additional, Mortensen, Uffe H., additional, Morty, Rory E., additional, Moss, Joel, additional, Motoshima, Hidemasa, additional, Mottram, Jeremy C., additional, Moura-da-Silva, Ana M., additional, Mudgett, Mary Beth, additional, Mundt, Egbert, additional, Murakami, Kazuo, additional, Murakami, Mario Tyago, additional, MurakamiMurofoshi, Kimiko, additional, Murao, Sawao, additional, Murphy, Gillian, additional, Murthy, M.R.N., additional, Muta, Tatsushi, additional, Myburgh, Elmarie, additional, Mzhavia, Nino, additional, Nabi, A.H.M. 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Published
2013
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48. Investigations into [[sigma].sup.B]-modulated regulatory pathways governing extracellular virulence determinant production in Staphylococcus aureus

Author

Shaw, Lindsey N., Aish, Joanne, Davenport, Jessica E., Brown, Melanie C., Lithgow, James K., Simmonite, Kay, Crossley, Howard, Travis, James, Potempa, Jan, and Foster, Simon J.

Subjects
Staphylococcus aureus -- Physiological aspects, Staphylococcus aureus -- Genetic aspects, Chromosome deletion -- Research, Genetic research, Biological sciences
Abstract

The commonly used Staphylococcus aureus laboratory strain 8325-4 bears a naturally occurring 11-bp deletion in the [[sigma].sup.B]-regulating phosphatase rsbU. We have previously published a report (M. J. Horsburgh, J. L. Aish, I. J. White, L. Shaw, J. K. Lithgow, and S. J. Foster, J. Bacteriol. 184:5457-5467, 2002) on restoring the rsbU deletion, producing a [[sigma].sup.B]-functional 8325-4 derivative, SH1000. SH1000 is pleiotropically altered in phenotype from 8325-4, displaying enhanced pigmentation, increased growth yields, and a marked decrease in secreted exoproteins. This reduction in exoprotein secretion appears to result from a sixfold reduction in agr expression. In this study we have undertaken transposon mutagenesis of SH1000 to identify components involved in the modulation of extracellular proteases and [alpha]-hemolysin compared to 8325-4. In total, 13 genes were identified displaying increased [alpha]-hemolysin transcription and extracellular proteolysis. Phenotypic analysis revealed that each mutant also had decreased pigmentation and a general increase in protein secretion. Interestingly this phenotype was not identical in each case but was variable from mutant to mutant. None of the genes identified encoded classic regulatory proteins but were predominantly metabolic enzymes involved in amino acid biosynthesis and transport. Further analysis revealed that all of these mutations were clustered in a 35-kb region of the chromosome. By complementation and genetic manipulation we were able to demonstrate the validity of these mutations. Interestingly transcriptional analysis revealed that rather than being regulated by [[sigma].sup.B], these genes appeared to have a role in the regulation of [[sigma].sup.B] activity. Thus, we propose that the loss of individual genes in this chromosomal hot spot region results in a destabilization of cellular harmony and disruption of the [[sigma].sup.B] regulatory, cascade.

Published
2006

49. Cytoplasmic control of premature activation of a secreted protease zymogen: deletion of staphostatin B (SspC) in Staphylococcus aureus 8325-4 yields a profound pleiotropic phenotype

Author

Shaw, Lindsey N., Golonka, Ewa, Szmyd, Grzegorz, Foster, Simon J., Travis, James, and Potempa, Jan

Subjects
Proteins -- Research, Pleiotropy -- Research, Staphylococcus aureus -- Genetic aspects, Genetic research, Biological sciences
Abstract

The cytoplasmic protein SspC of Staphylococcus aureus, referred to as staphostatin B, is a very specific, tightly binding inhibitor of the secreted protease staphopain B (SspB). SspC is hypothesized to protect intracellular proteins against proteolytic damage by prematurely folded and activated staphopain B (M. Rzychon, A. Sabat, K. Kosowska, J. Potempa, and A. Dubin, Mol. Microbiol. 49:1051-1066, 2003). Here we provide evidence that elimination of intracellular staphopain B activity is indeed the function of SspC. An isogenic sspC mutant of S. aureus 8325-4 exhibits a wide range of striking pleiotropic alterations in phenotype, which distinguish it from the parent. These changes include a defect in growth, a less structured peptidoglycan layer within the cell envelope, severely decreased autolytic activity, resistance to lysis by S. aureus phages, extensively diminished sensitivity to lysis by lysostaphin, the ability to form a biofilm, and a total lack of extracellular proteins secreted into the growth media. The same phenotype was also engineered by introduction of sspB into an 8325-4 sspBC mutant. In contrast, sspC inactivation in the SH1000 strain did not yield any significant changes in the mutant phenotype, apparently due to strongly reduced expression of sspB in the sigma B-positive background. The exact pathway by which these diverse aberrations are exerted in 8325-4 is unknown, but it is apparent that a very small amount of staphopain B (less than 20 ng per 200 [micro]g of cell proteins) is sufficient to bring about these widespread changes. It is proposed that the effects observed are modulated through the proteolytic degradation of several cytoplasmic proteins within cells lacking the inhibitor. Seemingly, some of these proteins may play a role in protein secretion; hence, their proteolytic inactivation by SspB has pleiotropic effects on the SspC-deficient mutant.

Published
2005

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