DOCSLIB.ORG

(12) United States Patent (10) Patent No.: US 9,078,860 B2 Szkudlinski Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) United States Patent (10) Patent No.: US 9,078,860 B2 Szkudlinski Et Al US00907886OB2 (12) United States Patent (10) Patent No.: US 9,078,860 B2 Szkudlinski et al. (45) Date of Patent: Jul. 14, 2015 (54) VEGF ANALOGS 6,020,473 A 2/2000 Keytet al. 6,057,428 A * 5/2000 Keytet al. ..................... 530.399 (71) Applicant: Trophogen Inc., Rockville, MD (US) 2: R R388 Rita etal (72) Inventors: Mariusz W. Szkudlinski, Rockville, g: R 839; Snowski et al. MD (US); Bruce D. Weintraub, 6,291,740 B1 9, 2001 Bremel et al. Rockville, MD (US) 6,361,992 B1 3/2002 Szkudlinski et al. 6,475,796 B1 1 1/2002 Pollitt et al. (73) Assignee: Trophogen, Inc., Rockville, MD (US) 3. R 1 838, (his et al. 7.005.505 B 2.2006 Keytet al. (*) Notice: Subject to any disclaimer, the term of this 2001, 0046521 A1 11, 2001 E. al. patent is extended or adjusted under 35 2003/0064922 A1 4/2003 Nissen et al. U.S.C. 154(b) by 0 days. 2004/0265972 A1 12/2004 Weintraub et al. 2005.0054036 A1 3/2005 Bates et al. 21) Appl. No.: 14/312,446 (21) App 9 FOREIGN PATENT DOCUMENTS (22) Filed: Jun. 23, 2014 JP 1998-511557 11, 1998 O O JP 2000-507456 6, 2000 (65) Prior Publication Data JP 2001-5.17075 10, 2001 JP 2003-5 17275 5, 2003 US 2014/0308264 A1 Oct. 16, 2014 WO 90.08832 8, 1990 WO 97.08313 3, 1997 Related U.S. Application Data WO 98,07832 2, 1998 WO OOf 17360 3, 2000 (62) Division of application No. 12/089,296, filed as WO OO,25805 5, 2000 application No. PCT/US2006/039181 on Oct. 6, 2006, WO 2005/042575 5, 2005 now Pat. No. 8,759,285. WO 2005, O724.17 8, 2005 (60) Provisional application No. 60/808,106, filed on May OTHER PUBLICATIONS 25, 2006, provisional application No. 60/723,917, Keytet al., “Identification of vascular endothelial growth factor deter filed on Oct. 6, 2005. minants for binding KDR and FLT-1 receptors. Generation of recep tor-selective VEGF variants by site-directed mutagenesis,” Journal of (51) Int. Cl. Biological Chemistry, 271 (10):5638-5646 (1998). A6 IK38/8 (2006.01) Siemeister et al., “An antagonistic vascular endothelial growth factor A6 IK38/6 (2006.01) (VEGF) variant inhibits VEGF-stimulated receptor A6 IK38/17 (2006.01) autophosphorylation and proliferation of human endothelial cells.” C07K I4/475 (2006.01) Proc. Natl Acad Sci USA, 95(8): 4625-4629 (1998). C07K I4/52 (2006.01) Lietal. “Receptor-selective Variants of Human Vascular Endothelial A6 IK 45/06 (2006.01) Growth Factor.” Journal of Biological Chemistry, 275 (38): 29823-8 A61 K38/00 (2006.015 (1998). (52) U.S. Cl. * cited by examiner CPC ............. A61K 38/1866 (2013.01); A61K 45/06 (2013.01); C07K 14/475 (2013.01); C07K Primary Examiner — Christine J Saoud 14/52 (2013.01); A61 K38/00 (2013.01) Assistant Examiner — Jon M Lockard (58) Field of Classification Search (74) Attorney, Agent, or Firm — Morgan Lewis & Bockius None LLP See application file for complete search history. (57) ABSTRACT (56) References Cited Modified VEGF proteins that inhibit VEGF-mediated activa U.S. PATENT DOCUMENTS tion or proliferation of endothelial cells are disclosed. The analogs may be used to inhibit VEGF-mediated activation of 4.902,505 A 2/1990 Pardridge et al. endothelial cells in angiogenesis-associated diseases Such as 5,008,050 A 4, 1991 Cullis et al. 5,017,566 A 5, 1991 Bodor cancer, inflammatory diseases, eye diseases, and skin disor 5,380,531 A 1/1995 Chakrabarti et al. ders. 5,604,198 A 2f1997 Poduslo et al. 5,612,034 A 3/1997 Pouletty et al. 22 Claims, 6 Drawing Sheets U.S. Patent Jul. 14, 2015 Sheet 1 of 6 US 9,078,860 B2 Figure 1A Binding of VEGF mutants&WT to imobilized KOR-FC 2500 e 83K 2000 WT 1500 5 1000 500 O 10-6 10-6 10-4 10-3 10-2 10-1 100 VEGF(ug/ml) Figure 1B HUVEC-2 Cell Proliferation Assay-Glo 225 Wt 200 o 83K 175 s S 150 O 125 SS 100 75 HTTTo TTTIn-Tim-Trim-Trim-rrttem-rm 0 10-13 10-12 10-11 10-10 10-0 0-0 0- 0-8 VEGF (M) U.S. Patent Jul. 14, 2015 Sheet 2 of 6 US 9,078,860 B2 Figure 2A Yeast VEGF Mutants Binding Assay 125 e Y-VEGF A3H 100 E44R 75 O O HTTTwo-TTTTwo-rrnu-TTTTTTm-rrm-Trium 0 1013 10-12 10-11 101 100 10 10-7 10-8 VEGF (M) Figure 2B HUVEC-2 Cell Proliferation Assay-Glo 225 Wt 200 o E44R 175 150 125 100 - 0 10-13 10-1210-11 10-10 0-0 0-0 0-7 10-8 VEGF (M) U.S. Patent Jul. 14, 2015 Sheet 3 of 6 US 9,078,860 B2 Figure 3A Yeast VEGF Mutants Binding Assay 125 e Y-VEGF A3 100 a EE72/73RR 75 SO 25 0 1-S 1012 101 10-10 10 0 107 10 VEGF (M) Figure 3B HUVEC-2 Cell Proliferation Assay-Glo 225 Wt 200 o EE7273/RR 175 150 125 10-G =c 75 -trator TTTTTTTTTTTTTTTTTTo-Trp-rate 0 10-13 10-12 101110-10 10-0 10-s 10-7 10-8 VEGF (M) U.S. Patent Jul. 14, 2015 Sheet 5 of 6 US 9,078,860 B2 G?un61-I ?onu?suoo?seeA6u?pu?gHQXÁessW 0000Z (INdo) punoq-93A-l U.S. Patent Jul. 14, 2015 Sheet 6 of 6 US 9,078,860 B2 eunfil-l9 ?sea?10.nu?suooNCIX6u?pu?ºKessy 0000Z 0000|| (Wido) punoq-93A-l US 9,078,860 B2 1. 2 VEGF ANALOGS KDR is the predominant receptor in angiogenic signaling, whereas Flt-1 is associated with the regulation of blood vessel CROSS-REFERENCE TO RELATED morphogenesis and Flt-4 regulates lymphangiogenesis. APPLICATIONS These receptors are expressed almost exclusively on endot helial cells, with a few exceptions such as the expression of This application claims the benefit of U.S. Provisional Flt-1 in monocytes where it mediates chemotaxis (Barleon et Application No. 60/723,917, filed Oct. 6, 2005, and U.S. al., 1996, Blood. 87: 3336-3343). Provisional Application No. 60/808,106, filed May 25, 2006, VEGF receptors are closely related to Fms, Kit and PDGF which are herein incorporated by reference in their entireties. receptors. They consist of seven extracellular immunoglobu 10 lin (Ig)-like domains, a transmembrane (TM) domain, a regu SEQUENCE LISTING SUBMISSION VIA latory juxtamembrane domain, an intracellular tyrosine EFS-WEB kinase domain interrupted by a short peptide, the kinase insert domain, followed by a sequence carrying several tyrosine A computer readable text file, entitled “056815-5005-01 residues involved in recruiting downstream signaling mol SequenceListing..txt created on or about Jun. 20, 2014, with 15 ecules. Mutation analysis of the extracellular domains of a file size of about 146 kb contains the sequence listing for this Flt-1 and KDR show that the second and third Ig-like domains application and is hereby incorporated by reference in its constitute the high-affinity ligand-binding domain for VEGF entirety. with the first and fourth Ig domains apparently regulating ligand binding and receptor dimerization, respectively FIELD OF INVENTION (Davis-Smyth et al., 1998, J. Biol. Chem. 273: 3216-3222: Fuh et al., 1998, J. Biol. Chem. 273: 11197-11204; and Shin This application relates to the design and use of vascular kai et al., 1998, J. Biol. Chem. 273:31283-31288). Receptor endothelial growth factor (VEGF) analogs as VEGF receptor tyrosine kinases are activated upon ligand-mediated receptor antagonists to inhibitor reduce angiogenesis for the treatment dimerization (Hubbard, 1991, Prog. Biophys. Mol. Biol. 71: of conditions and diseases associated with angiogenesis. The 25 343-358: Jiang and Hunter, 1999, Curr. Biol. 9: R568-R571; application also discloses VEGF analogs that exhibit and Lemmon and Schlessinger, 1998, Methods Mol. Biol. 84: increased receptor binding affinity to native receptors such as 49-71). Signal specificity of VEGF receptors is further modu KDR. lated upon recruitment of coreceptors, such as neuropilins, heparin Sulfate, integrins or cadherins. BACKGROUND OF INVENTION 30 VEGF molecules interact with one or more tyrosine kinase receptors during angiogenesis. For instance, VEGF-A acts Vascular endothelial growth factors (VEGFs) regulate predominantly through KDR and Flt-1. VEGF-C and blood and lymphatic vessel development. They are predomi VEGF-D similarly are specific ligands for KDR and nantly produced by endothelial, hematopoietic and stromal VEGFR3. PIGF and VEGF-B are believed to bind only to cells in response to hypoxia and stimulation with growth 35 Flt-1. Viral VEGF-E variants activate KDR, VEGF-F variants factors such as transforming growth factors, interleukins and interact with either VEGFR3 or KDR. platelet-derived growth factor. In addition to the two classical receptors, there are several In mammals, VEGFs are encoded by a family of genes and membrane or soluble receptors modulating VEGF bioactivity include VEGF-A, VEGF-B, VEGF-C, VEGF-D and Placenta and angiogenesis. For instance, neuropilin-1 and neuropilin-2 like Growth Factor (PIGF). Highly related proteins include 40 interact with both KDR and Flt-1, respectively, stimulating orf virus-encoded VEGF-like proteins referred to as VEGF-E signaling of those receptors. Isoforms of VEGF-A, VEGF-B, and a series of snake venoms referred to as VEGF-F. VEGFs PlGF-2 have been shown to bind to neuropilin-1 (Soker et al., and VEGF-related proteins are members of the Platelet 1998, Cell.92: 735-745; Makinen et al., 1999, J.
Load more

Recommended publications
  • Introduction to Bacteriology and Bacterial Structure/Function
    INTRODUCTION TO BACTERIOLOGY AND BACTERIAL STRUCTURE/FUNCTION LEARNING OBJECTIVES To describe historical landmarks of medical microbiology To describe Koch’s Postulates To describe the characteristic structures and chemical nature of cellular constituents that distinguish eukaryotic and prokaryotic cells To describe chemical, structural, and functional components of the bacterial cytoplasmic and outer membranes, cell wall and surface appendages To name the general structures, and polymers that make up bacterial cell walls To explain the differences between gram negative and gram positive cells To describe the chemical composition, function and serological classification as H antigen of bacterial flagella and how they differ from flagella of eucaryotic cells To describe the chemical composition and function of pili To explain the unique chemical composition of bacterial spores To list medically relevant bacteria that form spores To explain the function of spores in terms of chemical and heat resistance To describe characteristics of different types of membrane transport To describe the exact cellular location and serological classification as O antigen of Lipopolysaccharide (LPS) To explain how the structure of LPS confers antigenic specificity and toxicity To describe the exact cellular location of Lipid A To explain the term endotoxin in terms of its chemical composition and location in bacterial cells INTRODUCTION TO BACTERIOLOGY 1. Two main threads in the history of bacteriology: 1) the natural history of bacteria and 2) the contagious nature of infectious diseases, were united in the latter half of the 19th century. During that period many of the bacteria that cause human disease were identified and characterized. 2. Individual bacteria were first observed microscopically by Antony van Leeuwenhoek at the end of the 17th century.
    [Show full text]
  • Staphylococcus Aureus Exfoliative Toxins: How They Cause Disease
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE To cite this article: JID 122:1070–1077, 2004 provided by Elsevier - Publisher Connector Published by the ology Progress in Dermatology Editor: Alan N. Moshell, M.D. Staphylococcus aureus exfoliative toxins: How they cause disease. Lisa R.W. Plano, M.D., Ph.D. Departments of Pediatrics and Microbiology & Immunology University of Miami School of Medicine, Miami, Florida Abbreviations: cell surface molecules associated with adhesion and BI- bullous impetigo multiple antibiotic resistances including methicillin and ET- exfoliative toxins vancomycin resistance (Centers for Disease Control and EDIN- epidermal cell differentiation inhibitor Prevention, 1997; 2000a; 2000b), all contributing to the ETA- exfoliative toxin A (epidermolysisn A, exfoliatin A) pathogenicity of these organisms. A minimum of 34 ETB- exfoliative toxin B (epidermolysisn B, exfoliatin B) different extracellular proteins are produced by S. ETD- exfoliative toxin D (epidermolysisn D, exfoliatin D) aureus, and many of these have defined roles in the PF- pemphigus foliaceus pathogenesis of their associated diseases (Iandolo, SSSS- Staphylococcal scalded skin syndrome, (pemphi- 1989). Infectious conditions caused by these organisms gus neonatorum, dermatitis exfoliativa neonatorum, can be divided into three major categories; (i) superficial Ritter’s disease) skin infections, skin abcesses and wound infections TEN- toxic epidermal necrolysis including bullous impetigo (BI) and furuncles, (ii) systemic or infections of deep seeded tissues including osteomyelitis, endocarditis, pneumonia and sepsis, and Introduction (iii) conditions caused by intoxication with one of the General Microbiology: Staphylococci are hardy excreted toxins. Among the conditions caused by intoxi- Gram-positive cocci found as bacterial pathogens or cation with an exotoxin are toxic shock syndrome caused commensal organisms in both humans and animals.
    [Show full text]
  • Serine Proteases with Altered Sensitivity to Activity-Modulating
    (19) & (11) EP 2 045 321 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 08.04.2009 Bulletin 2009/15 C12N 9/00 (2006.01) C12N 15/00 (2006.01) C12Q 1/37 (2006.01) (21) Application number: 09150549.5 (22) Date of filing: 26.05.2006 (84) Designated Contracting States: • Haupts, Ulrich AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 51519 Odenthal (DE) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • Coco, Wayne SK TR 50737 Köln (DE) •Tebbe, Jan (30) Priority: 27.05.2005 EP 05104543 50733 Köln (DE) • Votsmeier, Christian (62) Document number(s) of the earlier application(s) in 50259 Pulheim (DE) accordance with Art. 76 EPC: • Scheidig, Andreas 06763303.2 / 1 883 696 50823 Köln (DE) (71) Applicant: Direvo Biotech AG (74) Representative: von Kreisler Selting Werner 50829 Köln (DE) Patentanwälte P.O. Box 10 22 41 (72) Inventors: 50462 Köln (DE) • Koltermann, André 82057 Icking (DE) Remarks: • Kettling, Ulrich This application was filed on 14-01-2009 as a 81477 München (DE) divisional application to the application mentioned under INID code 62. (54) Serine proteases with altered sensitivity to activity-modulating substances (57) The present invention provides variants of ser- screening of the library in the presence of one or several ine proteases of the S1 class with altered sensitivity to activity-modulating substances, selection of variants with one or more activity-modulating substances. A method altered sensitivity to one or several activity-modulating for the generation of such proteases is disclosed, com- substances and isolation of those polynucleotide se- prising the provision of a protease library encoding poly- quences that encode for the selected variants.
    [Show full text]
  • Targeting Staphylococcus Aureus Toxins: a Potential Form of Anti-Virulence Therapy
    toxins Review Targeting Staphylococcus aureus Toxins: A Potential form of Anti-Virulence Therapy Cin Kong 1, Hui-min Neoh 2 and Sheila Nathan 1,* 1 School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor Darul Ehsan, Malaysia; kong_cin@hotmail.com 2 UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, 56000 Cheras, Kuala Lumpur, Malaysia; hui-min@ppukm.ukm.edu.my * Correspondence: sheila@ukm.edu.my; Tel.: +60-3-8921-3862 Academic Editor: Yinduo Ji Received: 18 February 2016; Accepted: 10 March 2016; Published: 15 March 2016 Abstract: Staphylococcus aureus is an opportunistic pathogen and the leading cause of a wide range of severe clinical infections. The range of diseases reflects the diversity of virulence factors produced by this pathogen. To establish an infection in the host, S. aureus expresses an inclusive set of virulence factors such as toxins, enzymes, adhesins, and other surface proteins that allow the pathogen to survive under extreme conditions and are essential for the bacteria’s ability to spread through tissues. Expression and secretion of this array of toxins and enzymes are tightly controlled by a number of regulatory systems. S. aureus is also notorious for its ability to resist the arsenal of currently available antibiotics and dissemination of various multidrug-resistant S. aureus clones limits therapeutic options for a S. aureus infection. Recently, the development of anti-virulence therapeutics that neutralize S. aureus toxins or block the pathways that regulate toxin production has shown potential in thwarting the bacteria’s acquisition of antibiotic resistance. In this review, we provide insights into the regulation of S.
    [Show full text]
  • Wednesday Slide Conference 2008-2009
    PROCEEDINGS DEPARTMENT OF VETERINARY PATHOLOGY WEDNESDAY SLIDE CONFERENCE 2008-2009 ARMED FORCES INSTITUTE OF PATHOLOGY WASHINGTON, D.C. 20306-6000 2009 ML2009 Armed Forces Institute of Pathology Department of Veterinary Pathology WEDNESDAY SLIDE CONFERENCE 2008-2009 100 Cases 100 Histopathology Slides 249 Images PROCEEDINGS PREPARED BY: Todd Bell, DVM Chief Editor: Todd O. Johnson, DVM, Diplomate ACVP Copy Editor: Sean Hahn Layout and Copy Editor: Fran Card WSC Online Management and Design Scott Shaffer ARMED FORCES INSTITUTE OF PATHOLOGY Washington, D.C. 20306-6000 2009 ML2009 i PREFACE The Armed Forces Institute of Pathology, Department of Veterinary Pathology has conducted a weekly slide conference during the resident training year since 12 November 1953. This ever- changing educational endeavor has evolved into the annual Wednesday Slide Conference program in which cases are presented on 25 Wednesdays throughout the academic year and distributed to 135 contributing military and civilian institutions from around the world. Many of these institutions provide structured veterinary pathology resident training programs. During the course of the training year, histopathology slides, digital images, and histories from selected cases are distributed to the participating institutions and to the Department of Veterinary Pathology at the AFIP. Following the conferences, the case diagnoses, comments, and reference listings are posted online to all participants. This study set has been assembled in an effort to make Wednesday Slide Conference materials available to a wider circle of interested pathologists and scientists, and to further the education of veterinary pathologists and residents-in-training. The number of histopathology slides that can be reproduced from smaller lesions requires us to limit the number of participating institutions.
    [Show full text]
  • High Nasal Carriage Rate of Staphylococcus Aureus Containing Panton-Valentine Leukocidin- and EDIN-Encoding Genes in Community A
    High Nasal Carriage Rate of Staphylococcus aureus Containing Panton-Valentine leukocidin- and EDIN-Encoding Genes in Community and Hospital Settings in Burkina Faso Abdoul-Salam Ouedraogo, Catherine Dunyach-Remy, Aimée Kissou, Soufiane Sanou, Armel Poda, Carole Kyelem, Jérôme Solassol, Anne-Laure Bañuls, Philippe van de Perre, Rasmata Ouédraogo, et al. To cite this version: Abdoul-Salam Ouedraogo, Catherine Dunyach-Remy, Aimée Kissou, Soufiane Sanou, Armel Poda, et al.. High Nasal Carriage Rate of Staphylococcus aureus Containing Panton-Valentine leukocidin- and EDIN-Encoding Genes in Community and Hospital Settings in Burkina Faso. Frontiers in Microbiol- ogy, Frontiers Media, 2016, 7, pp.1406. 10.3389/fmicb.2016.01406. hal-01818967 HAL Id: hal-01818967 https://hal.archives-ouvertes.fr/hal-01818967 Submitted on 21 Sep 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License ORIGINAL RESEARCH published: 13 September 2016 doi: 10.3389/fmicb.2016.01406 High Nasal Carriage Rate of Staphylococcus aureus Containing Panton-Valentine leukocidin- and EDIN-Encoding Genes in Community and Hospital Settings in Burkina Faso Abdoul-Salam Ouedraogo 1, 2, 3, 4*, Catherine Dunyach-Remy 5, 6, Aimée Kissou 1, Soufiane Sanou 1, Armel Poda 1, Carole G.
    [Show full text]
  • Exfoliative Toxin Mediated Staphylococcal Scalded Skin Syndrome: a Review
    International Journal of Current Research and Review Review Article DOI: http://dx.doi.org/10.31782/IJCRR.2020.122212 Exfoliative Toxin Mediated Staphylococcal Scalded Skin Syndrome: A Review IJCRR 1 2 3 Section: Healthcare Gayathri Sunil , Meghana Vinod , Roshni PR Sci. Journal Impact Factor: 6.1 (2018) 1 ICV: 90.90 (2018) Student, Pharm D PB, Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi-682041, Kerala, India; 2Student, Pharm D PB, Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi-682041, Kerala, India; 3Assistant Professor Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Vishwa Vidyap- Copyright@IJCRR eetham, Kochi-682041, Kerala, India. ABSTRACT . Staphylococcal scalded skin syndrome (SSSS) is a rare dermatological condition associated with extensive desquamation by toxicogenic strains of staphylococcus aureus. The two known serotypes of exfoliative toxin namely A and B are responsible for this disease entity. Haematogenous dissemination of toxin cause extensive epidermal damage at sites distant to the infectious site. When considering all age ranges, SSSS is more prevalent in infants and children below 5 years but can occur at any age. Initially, symptoms include fever, malaise, dehydration followed by the tenderness of the skin with erythematous rash, flaccid blis- ters and bullae which may rupture on pressure, leaving superficial crusts. Despite a well-known clinical aspect, several cutane- ous diseases may be mistaken for SSSS. Therefore, rapid and definitive histopathological evaluation of the biopsy is essential to confirm the diagnosis. The prognosis is improved by adequate therapy, that is, aggressive fluid replacement, nutritional support and optimal antibacterial policy.
    [Show full text]
  • Action Et Contrôle Des Leucotoxines De Staphylococcus Aureus Sur Les Cellules Cibles Mira Tawk
    Action et contrôle des leucotoxines de Staphylococcus aureus sur les cellules cibles Mira Tawk To cite this version: Mira Tawk. Action et contrôle des leucotoxines de Staphylococcus aureus sur les cellules cibles. Bactériologie. Université de Strasbourg, 2014. Français. NNT : 2014STRAJ111. tel-01234206 HAL Id: tel-01234206 https://tel.archives-ouvertes.fr/tel-01234206 Submitted on 26 Nov 2015 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE DES SCIENCES DE LA VIE ET DE LA SANTE EA-7290 Virulence bactérienne précoce : fonctions cellulaires et contrôle de l'infection aiguë et subaiguë THÈSE présentée par : Mira TAWK soutenue le : 07 juillet 2014 pour obtenir le grade de : !"#$%&'($')R%+,-$&.,# '($'0#&1.2!%&3 Discipline/ Spécialité : V'# #2 S,2M A1.#!21 M-*M!3*'0#1 #2 C#**3*'0#1 "# * B'-*-%'# Action et contrôle des leucotoxines de Staphylococcus aureus sur les cellules cibles THÈSE dirigée par : Dr. PRÉVOST Gilles MCU-PH, Université de Strasbourg Pr. BOURCIER Tristan Professeur, Université de Strasbourg RAPPORTEURS : Pr. FREY Joachim PR-PUPH, Université de Berne Dr. LADANT Daniel DR, Institut Pasteur-Paris AUTRES MEMBRES DU JURY : Dr.
    [Show full text]
  • Bacterial Quorum Sensing: Its Role in Virulence and Possibilities for Its Control
    Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Bacterial Quorum Sensing: Its Role in Virulence and Possibilities for Its Control Steven T. Rutherford1 and Bonnie L. Bassler1,2 1Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544 2Howard Hughes Medical Institute, Chevy Chase, Maryland 20815 Correspondence: bbassler@princeton.edu Quorum sensing is a process of cell–cell communication that allows bacteria to share information about cell density and adjust gene expression accordingly. This process enables bacteria to express energetically expensive processes as a collective only when the impact of those processes on the environment or on a host will be maximized. Among the many traits controlled by quorum sensing is the expression of virulence factors by path- ogenic bacteria. Here we review the quorum-sensing circuits of Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, and Vibrio cholerae. We outline these canonical quorum-sensing mechanisms and how each uniquely controls virulence factor production. Additionally,we examine recent efforts to inhibit quorum sensing in these pathogens with the goal of designing novel antimicrobial therapeutics. uorum sensing (QS) is a bacterial cell–cell Despite differences in regulatory compo- Qcommunication process that involves the nents and molecular mechanisms, all known production, detection, and response to extra- QS systems depend on three basic principles. cellular signaling molecules called autoinducers First, the members of the community produce (AIs). AIs accumulate in the environment as the AIs, which are the signaling molecules. At low bacterial population density increases, and bac- cell density (LCD), AIs diffuse away, and, there- teria monitor this information to track changes fore, are present at concentrations below the in their cell numbers and collectively alter gene threshold required for detection.
    [Show full text]
  • Infection and Immunity
    INFECTION AND IMMUNITY Volume 13 Contents for March Number3 Bacterial and Mycotic Infections Analysis ofthe Cell Wall ofFive Strains ofMycobacterium tuberculosis BCG and of an Attenuated Human Strain, W 115. P. H. PHIET, JUANA WIETZERBIN, ELISE ZISSMAN, J. F. PETIT,* AND E. LEDERER ...... ..................... 677 Subcutaneous Multiplication of Exfoliatin-Producing Staphylococci. FRANK A. KAPRAL .............................................................. 682 Virulent Treponemapallidum: Aerobe or Anaerobe. JOEL B. BASEMAN,* JEAN C. NICHOLS, AND NANCY S. HAYES ......................................... 704 Bacterial Interference. III. Effects of Oral Antibiotics on the Normal Throat Flora and Its Ability to Interfere with Group A Streptococcus. CHRISTINE C. SANDERS,* W. EUGENE SANDERS, JR., AND DAVID J. HARROWE .... ......... 808 Relationship of Cellular Potential Hemolysin in Group A Streptococci to Extra- cellular Streptolysin S. G. B. CALANDRA, R. S. WHITT, AND R. M. COLE* .. 813 Germination of Candida albicans Induced by Proline. NINA DABROWA, SHARON S. S. TAXER, AND DEXTER H. HOWARD* ................................. 830 Pathological Features of Experimental Gonococcal Infection in Mice and Guinea Pigs. FRANCIS W. CHANDLER,* STEPHEN J. KRAUS, AND JOHN C. WATTS . 909 Growth and Effects of Ureaplasmas (T Mycoplasmas) in Bovine Oviductal Organ Cultures. 0. H. V. STALHEIM,* S. J. PROCTOR, AND J. E. GALLAGHER ..... 915 Unbalanced Growth and Macromolecular Synthesis in Streptococcus mutans FA-1. S. J. MATTINGLY, J. R. DIPERSIO, M. L. HIGGINS, AND G. D. SHOCKMAN* ... 941 Attachment of Mycoplasma pneumoniae to Respiratory Epithelium. DWIGHT A. POWELL, * PING C. Hu, MARION WILSON, ALBERT M. COLLIER, AND JOEL B. BASEMAN ........................................................... 959 Purification of Staphylococcal Alpha-Toxin by Adsorption Chromatography on Glass. PAUL CASSIDY AND SIDNEY HARSHMAN* ...... .................... 982 T Antigen of Streptococcus pyogenes: Isolation and Purification.
    [Show full text]
  • Distribution of Toxinogenic Methicillin-Resistant and Methicillin-Susceptible Staphylococcus Aureus from Different Ecological Ni
    toxins Article Distribution of Toxinogenic Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus from Different Ecological Niches in Algeria Assia Mairi 1,2 , Abdelaziz Touati 1, Alix Pantel 3, Karima Zenati 1, Alex Yahiaoui Martinez 3, Catherine Dunyach-Remy 3, Albert Sotto 4 and Jean-Philippe Lavigne 3,* 1 Laboratoire d’Ecologie Microbienne, FSNV, Université de Bejaia, Bejaia 06000, Algeria 2 National Institute of Health and Medical Research INSERM U1047, University of Montpellier, 30900 Montpellier, France 3 Department of Microbiology, CHU Nîmes, University of Montpellier, 30900 Montpellier, France 4 Department of Infectious Diseases, CHU Nîmes, University of Montpellier, 30900 Montpellier, France * Correspondence: jean.philippe.lavigne@chu-nimes.fr Received: 31 July 2019; Accepted: 21 August 2019; Published: 28 August 2019 Abstract: The diffusion of Panton–Valentine leukocidin (PVL)–positive methicillin-resistant S. aureus (MRSA) is a health problem in Algeria. The objectives of the study were to investigate the global distribution of methicillin-susceptible S. aureus (MSSA) and MRSA isolates in different ecological niches in this country. In total, 2246 samples were collected from humans, livestock, wild animals, pets, food products and the aquatic environment, from 12 Algerian provinces. A total of 312 S. aureus were detected from 2446 samples (12.7%) in the screened niches. We observed the emergence of toxinogenic S. aureus representing 41% of the isolates. Among them, we noted the diffusion of ST80-IV CA-MRSA PVL + strains isolated in human, animals, and food and genetic diversity of MSSA PVL + isolates. This study suggests an alarming dissemination of MRSA-ST80 PVL + in both human and extra-human sources in Algeria.
    [Show full text]
  • Botulinum Toxin
    Botulinum toxin From Wikipedia, the free encyclopedia Jump to: navigation, search Botulinum toxin Clinical data Pregnancy ? cat. Legal status Rx-Only (US) Routes IM (approved),SC, intradermal, into glands Identifiers CAS number 93384-43-1 = ATC code M03AX01 PubChem CID 5485225 DrugBank DB00042 Chemical data Formula C6760H10447N1743O2010S32 Mol. mass 149.322,3223 kDa (what is this?) (verify) Bontoxilysin Identifiers EC number 3.4.24.69 Databases IntEnz IntEnz view BRENDA BRENDA entry ExPASy NiceZyme view KEGG KEGG entry MetaCyc metabolic pathway PRIAM profile PDB structures RCSB PDB PDBe PDBsum Gene Ontology AmiGO / EGO [show]Search Botulinum toxin is a protein and neurotoxin produced by the bacterium Clostridium botulinum. Botulinum toxin can cause botulism, a serious and life-threatening illness in humans and animals.[1][2] When introduced intravenously in monkeys, type A (Botox Cosmetic) of the toxin [citation exhibits an LD50 of 40–56 ng, type C1 around 32 ng, type D 3200 ng, and type E 88 ng needed]; these are some of the most potent neurotoxins known.[3] Popularly known by one of its trade names, Botox, it is used for various cosmetic and medical procedures. Botulinum can be absorbed from eyes, mucous membranes, respiratory tract or non-intact skin.[4] Contents [show] [edit] History Justinus Kerner described botulinum toxin as a "sausage poison" and "fatty poison",[5] because the bacterium that produces the toxin often caused poisoning by growing in improperly handled or prepared meat products. It was Kerner, a physician, who first conceived a possible therapeutic use of botulinum toxin and coined the name botulism (from Latin botulus meaning "sausage").
    [Show full text]