DOCSLIB.ORG

(12) United States Patent (10) Patent No.: US 6,503,881 B2 Krieger 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 6,503,881 B2 Krieger Et Al USOO6503881B2 (12) United States Patent (10) Patent No.: US 6,503,881 B2 Krieger et al. (45) Date of Patent: *Jan. 7, 2003 (54) COMPOSITIONS AND METHODS FOR WO WO 97/08199 3/1997 TREATING INFECTIONS USING CATIONC WO WO 97/31942 9/1997 PEPTIDES ALONE OR IN COMBINATION W W SS 6.C. WITH ANTIBIOTICS WO WO 99/43357 9/1999 (75) Inventors: Timothy J. Krieger, Richmond (CA); OTHER PUBLICATIONS Robert Taylor, Surrey (CA); Douglas Erfle, Vancouver (CA); Janet R. Uchida et al., Pept. Chem. Volume date 1995, 33rd pp. Fraser, Vancouver (CA); Michael H. P. 229-232, 1996.* West, Vancouver (CA); Patricia J. Bundgaard (Ed) “Design of Prodrugs” (Elsevier Publishing) McNichol, Coquitlam (CA) pp. 1-24, 1983.* Chalk et al., “Purification of An Insect Defensin from the 73) Assignee:9. Micrologix Biotech Inc., Vancouver Mosquito, Aedes aegypti, ' Insect Biochem. Molec. Biol. (CA) 24(4):403-410, 1994. Chalk et al., “Full Sequence and Characterization of Two * ) Notice: Subject to anyy disclaimer, the term of this Insect Defensins: Immune Peptides from the Mosquito patent is extended or adjusted under 35 Aedes Aegypti,” Proc. R. Soc. Land. B. 261 (1361):217-221, U.S.C. 154(b) by 0 days. 1995. Darveau et al., “B-Lactam Antibiotics Potentiate Magainin This patent is Subject to a terminal dis 2 Antimicrobial Activity In Vitro and In Vivo, Antimicro claimer. bial Agents & Chemotherapy 35(6):1153–1159, 1991. Engström et al., “The Antibacterial Effect of Attacins from (21) Appl. No.: 09/030,619 the Silk Moth Hyalophoracecropia is Directed Against the Outer Membrane of Escherichia coli,” EMBO J. (22) Filed: Feb. 25, 1998 3(13):3347–3351, 1984. Hancock, “The Role of Fundamental Research and Biotech (65) Prior Publication Data nology in Finding Solutions to the Global Problem of US 2002/0035061 A1 Mar. 21, 2002 Antibiotic Resistance,” Clin. Infectious Diseases 24(Supp 1)S148–S150, 1997. Related U.S. Application Data Piers et al., “Improvement of Outer Membrane-Permeabi lizing and Lipopolysaccharide-Binding Activities of an (63) Continuation-in-part of application No. 08/915,314, filed on Antimicrobial Cationic Peptide by C-Terminal Modifica Aug. 20, 1997, now Pat. No. 6,180,604 (60) Provisional application No. 60/060,099, filed on Sep. 26, tion,” Antimicrobial Agents & Chemotherapy 1997, provisional application No. 60/040,649, filed on Mar. 38(10):2311-2316, 1994. 10, 1997, provisional application No. 60/034.949, filed on Vaara, “The Outer Membrane as the Penetration Barrier Jan. 13, 1997, and provisional application No. 60/024.754, Against Mupirocin in Gram-Negative Enteric Bacteria, J. filed on Aug. 21, 1996. Antimicrob. Chemother, 29(2):221-222, 1992. Vaara, “Agents That Increase the Permeability of the Outer (51) Int. Cl. ........................... A61K 38/03; CO7K 7/00 Membrane,” Microbiological Reviews 56(3):395-411, 1992. (52) U.S. Cl. ............................... 514/2; 514/17; 514/18; Vaara and Porro, “Group of Peptides That Act Synergisti 514/19; 514/20, 530/324; 530/325; 530/326; cally with Hydrophobic Antibiotics Against Gram-Negative 530/327; 530/328; 530/329; 530/330 Enteric Bacteria, Antimicrobial Agents & Chemotherapy (58) Field of Search ................................. 530/324-330; 40(8): 1801–1805, 1996. 514/2, 17–20 Vaara and Vaara, “Polycations Sensitive Enteric Bacteria to Antibiotics,” Antimicrobial Agents & Chemotherapy (56) References Cited 24(1):107–113, 1983. Vaara and Vaara, “Sensitization of Gram-Negative Bacteria U.S. PATENT DOCUMENTS to Antibiotics and Complement by a Nontoxic Oligopep 4,510,132 A 4/1985 Vaara .......................... 514/11 tide,” Nature 303:526–528, 1983. 5,324,716 A 6/1994 Selsted et al. ................ 514/14 5,359,030 A 10/1994 Ekwuribe ..... ... 530/303 (List continued on next page.) 5,438,040 A 8/1995 Ekwuribe ...................... 514/3 5,523.288 A 6/1996 Cohen et al. ................. 514/12 Primary Examiner Bennett Celsa 5,547,939 A 8/1996 Selsted ........................ 514/14 (74) Attorney, Agent, or Firm-Seed Intellectual Property 5,578,572 A 11/1996 Horwitz et al. ............... 514/12 Law Group PLLC 5,593.866 A 1/1997 Hancock et al. ........... 435/69.7 6,191,254 B1 2/2001 Falla et al. ................. 530/300 (57) ABSTRACT FOREIGN PATENT DOCUMENTS Compositions and methods for treating infections, especially bacterial infections, are provided. Indolicidin peptide ana EP 590 O70 B1 2/1998 logues containing at least two basic amino acids are pre WO WO 91/12815 9/1991 WO WO 92/22308 12/1992 pared. The analogues are administered as modified peptides, WO WO95/22338 8/1995 preferably containing photo-oxidized Solubilizer. WO WO 96/38473 12/1996 WO WO 97/04796 2/1997 62 Claims, 22 Drawing Sheets US 6,503,881 B2 Page 2 OTHER PUBLICATIONS Subbalakshmi and Sitaram, “Mechanism of Antimicrobial Vaara and Vaara, “Ability of Cecropin B to Penetrate the Action of Indolicidin,” FEMS Microbiology Letters Enterobacterial Outer Membrane,” Antimicrobial Agents & 160:91-96, 1998. Chemotherapy 38(10):2498-2501, 1994. Subbalakshmi et al., “Interaction of Indolicidin, a 13-Resi Falla et al., “Mode of Action of the Antimicrobial Peptide due Peptide Rich in Tryptophan and Proline and its Ana Indolicidin,” The Journal of Biological Chemistry 271 (32): logues with Model Membranes,” J. Biosci. 23(1):9-13, 19298–19303, Aug. 9, 1996. 1998. Falla and Hancock, “Improved Activity of a Synthetic Subbalakshmi et al., “Requirements for antibacterial and Indolicidin Analog,” Antimicrobial Agents and Chemo hemolytic activities in the bovine neutrophil derived therapy 41(4): 771–775, 1997. 13-residue peptide indolicidin,” FEBS Letters 395(1): Ladokhin et al., “CD Spectra of Indolicidin Antimicrobial 48-52, 1996. Peptides Suggest Turns, Not Polyproline Helix,” Biochem Tanchak et al., “Tryptophanins: Isolation and Molecular istry 38:12313–12319, 1999. Characterization of Oat cDNA Clones Encoding Proteins Lawyer et al., “Antimicrobial Activity of a 13 Amino Acid Structurally Related to Puroindoline and Wheat Grain Soft Tryptophan-Rich Peptide Derived From a Putative Porcine ness Proteins,” Plant Science 137:173–184, 1998. Precursor Protein of a Novel Family of Antibacterial Pep Uchida et al., “Stucture-Activity of Antibacterial Peptide tides.” FEBS Letters 390:95–98, 1996. Indolicidin and Analogs.” Peptide Science, pp. 221-224, Robinson, Jr. et al., “Anti-HIV-1 Activity of Indolicidin, an 1998. Antimicrobial Peptide from Neutrophils,” Journal of Leu Van Abel et al., “Synthesis and Characterization of Indoli kocyte Biology 63:94-100, 1998. cidin, a Tryptophan-Rich Antimicrobial Peptide from Selsted et al., “Indolicidin, a Novel Bactericidal Tridecapep Bovine Neutrophils,” Int. J. Peptide Protein Res. tide Amide from Neutrophils.” The Journal Of Biological 45:401–409, 1995. Chemistry 267(7):4292–4295, Mar. 5, 1992. Wakabayashi et al., “N-Acylated and D Encantiomer Selsted et al., “Purification, Characterization, Synthesis and Derivatives of a Nonamer Core Peptide of Lactoferricin B cDNA Cloning of Indolicidin: A Tryptophan-Rich Micro Showing Improved Antimicrobial Activity,” Antimicrobial bicidal Tridecapeptide from Neutrophils,” Proceedings of the 12" American Peptide Symposium, Jun. 16–21, 1991, Agents And Chemotherapy 43(5):1267-1269, May 1999. Cambridge, MA, pp. 905–907. * cited by examiner U.S. Patent Jan. 7, 2003 Sheet 1 of 22 US 6,503,881 B2 U.S. Patent Jan. 7, 2003 Sheet 2 of 22 US 6,503,881 B2 Time Kill Assay: w MB 11 CN (64 ug/ml) vs. S. aureus SAO6 s >< 14 -- CONTROL 1 A 12 --0-- CONTROL 2 2 10 -A-TEST 1 S. 8 --o-- TEST 2 c 6 SP 4. 2 2. C O S O 10 20 30 60 120 180 240 24h Fig. 3A TIME (MIN) Time Kill Assay: MB 11 F4CN (8 ug/ml) vs. S. aureus SAO6 se X -- CONTROL 1 2 --0-- CONTROL 2 2 -A-TEST 1 9 --0-- TEST 2 s 5 2. - F. S O 10 20 30 60 120 180 240 24h Fig. 3B TIME (MIN) Time Kill Assay: MB 11 B70N (16 ug/ml) vs. S. aureus SA06 s > 2. -- CONTROL 1 2 16 --0-- CONTROL 2 2. 1: -A-TEST 1 Se 10 - - - - - TEST 2 8 S2 6 4 2 2 C O S O 1 O 20 30 60 120 180 240 24h Fig. 3C TIME (MIN) U.S. Patent Jan. 7, 2003 Sheet 3 of 22 US 6,503,881 B2 MB 11 F4CN at its MIC against S. aureus SAO6 -O-CONTROL 3 Logo reduction O-TEST O 10 20 30 60 120 180 240 24h Time (min) Fig. 3D MB 26 & Vancomycin in Combination Against E. faecium EFMO17 --GROWTH CONTROL -O-MB 26 (1/2MIC) -O-Vancomycin (1/8 MIC) -HMB 26 + Wanc, O 15 30 45 60 120 180 240 24h Time (min) Fig. 3E U.S. Patent Jan. 7, 2003 Sheet 4 of 22 US 6,503,881 B2 L. 120 g r c 100 Y f W 2 80 - 2 60 1. gt 40 - 20 O 200 400 600 800 PEPTIDE SOLUTION CONCENTRATION (ug/ml) Fig. 4 MB 1 OB in Formulations C1 and D FREE PEPTIDE O.O7 0.07 100 100 0.06 0.06 0.05 0.05 0.04 0.04 i. 0.03 50 SS 0.05 50 ge 0.02 0.02 FREE PEPTIDE 0.01 0.01 0.00 0.00 O.O 2.5 5.0 7.5 O.O 2.5 5.0 7.5 MN. MN. Fig. 5A Fig. 5B U.S. Patent Jan. 7, 2003 Sheet 5 of 22 US 6,503,881 B2 CD Spectra of MBI 1CN / 5 O m 5 -10 -0- buffer -- POPC liposomes - 15 -20 195 205 215 225 235 WAVELENGTH (nm) CD Spectra of MB 11 B7CN -0- Free -- Free +PC/PG 195 205 215 225 235 WAVELENGTH (nm) Fig.
Load more

Recommended publications
  • Increased Biological Activity of Aneurinibacillus Migulanus Strains Correlates with the Production of New Gramicidin Secondary Metabolites
    fmicb-08-00517 April 5, 2017 Time: 15:34 # 1 ORIGINAL RESEARCH published: 07 April 2017 doi: 10.3389/fmicb.2017.00517 Increased Biological Activity of Aneurinibacillus migulanus Strains Correlates with the Production of New Gramicidin Secondary Metabolites Faizah N. Alenezi1,2, Imen Rekik2, Ali Chenari Bouket2,3, Lenka Luptakova2,4, Hedda J. Weitz1, Mostafa E. Rateb5, Marcel Jaspars6, Stephen Woodward1 and Lassaad Belbahri2,7* 1 Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK, 2 NextBiotech, Rue Ali Edited by: Belhouane, Agareb, Tunisia, 3 Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Peter Neubauer, Japan, 4 Department of Biology and Genetics, Institute of Biology, Zoology and Radiobiology, University of Veterinary Technische Universität Berlin, Medicine and Pharmacy, Košice, Slovakia, 5 School of Science and Sport, University of the West of Scotland, Paisley, UK, Germany 6 Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Aberdeen, UK, 7 Laboratory of Soil Biology, Reviewed by: University of Neuchatel, Neuchatel, Switzerland Sanna Sillankorva, University of Minho, Portugal The soil-borne gram-positive bacteria Aneurinibacillus migulanus strain Nagano shows Jian Li, University of Northwestern – St. Paul, considerable potential as a biocontrol agent against plant diseases. In contrast, USA A. migulanus NCTC 7096 proved less effective for inhibition of plant pathogens. Nagano Maria Lurdes Inacio, Instituto Nacional de Investigação strain exerts biocontrol activity against some gram-positive and gram-negative bacteria, Agrária e Veterinária, Portugal fungi and oomycetes through the production of gramicidin S (GS). Apart from the *Correspondence: antibiotic effects, GS increases the rate of evaporation from the plant surface, reducing Lassaad Belbahri periods of surface wetness and thereby indirectly inhibiting spore germination.
    [Show full text]
  • Molecular Docking Studies of a Cyclic Octapeptide-Cyclosaplin from Sandalwood
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 11 June 2019 doi:10.20944/preprints201906.0091.v1 Peer-reviewed version available at Biomolecules 2019, 9; doi:10.3390/biom9040123 Molecular Docking Studies of a Cyclic Octapeptide-Cyclosaplin from Sandalwood Abheepsa Mishra1, 2,* and Satyahari Dey1 1Plant Biotechnology Laboratory, Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur-721302, West Bengal, India; [email protected] (A.M.); [email protected] (S.D.) 2Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA *Correspondence: [email protected]; Tel.:+1(518) 881-9196 Abstract Natural products from plants such as, chemopreventive agents attract huge attention because of their low toxicity and high specificity. The rational drug design in combination with structure based modeling and rapid screening methods offer significant potential for identifying and developing lead anticancer molecules. Thus, the molecular docking method plays an important role in screening a large set of molecules based on their free binding energies and proposes structural hypotheses of how the molecules can inhibit the target. Several peptide based therapeutics have been developed to combat several health disorders including cancers, metabolic disorders, heart-related, and infectious diseases. Despite the discovery of hundreds of such therapeutic peptides however, only few peptide-based drugs have made it to the market. Moreover, until date the activities of cyclic peptides towards molecular targets such as protein kinases, proteases, and apoptosis related proteins have never been explored. In this study we explore the in silico kinase and protease inhibitor potentials of cyclosaplin as well as study the interactions of cyclosaplin with other cancer-related proteins.
    [Show full text]
  • Harnessing the Power of Bacteria in Advancing Cancer Treatment
    International Journal of Molecular Sciences Review Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment Shruti S. Sawant, Suyash M. Patil, Vivek Gupta and Nitesh K. Kunda * Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Jamaica, NY 11439, USA; [email protected] (S.S.S.); [email protected] (S.M.P.); [email protected] (V.G.) * Correspondence: [email protected]; Tel.: +1-718-990-1632 Received: 20 September 2020; Accepted: 11 October 2020; Published: 14 October 2020 Abstract: Conventional anti-cancer therapy involves the use of chemical chemotherapeutics and radiation and are often non-specific in action. The development of drug resistance and the inability of the drug to penetrate the tumor cells has been a major pitfall in current treatment. This has led to the investigation of alternative anti-tumor therapeutics possessing greater specificity and efficacy. There is a significant interest in exploring the use of microbes as potential anti-cancer medicines. The inherent tropism of the bacteria for hypoxic tumor environment and its ability to be genetically engineered as a vector for gene and drug therapy has led to the development of bacteria as a potential weapon against cancer. In this review, we will introduce bacterial anti-cancer therapy with an emphasis on the various mechanisms involved in tumor targeting and tumor suppression. The bacteriotherapy approaches in conjunction with the conventional cancer therapy can be effective in designing novel cancer therapies. We focus on the current progress achieved in bacterial cancer therapies that show potential in advancing existing cancer treatment options and help attain positive clinical outcomes with minimal systemic side-effects.
    [Show full text]
  • Review Cyclic Peptides on a Merry‐
    Review Cyclic Peptides on a Merry-Go-Round; Towards Drug Design Anthi Tapeinou,1 Minos-Timotheos Matsoukas,2 Carmen Simal,1 Theodore Tselios1 1Department of Chemistry, University of Patras, 26500, Patras, Greece 2Department of Biostatistics, Laboratory of Computational Medicine, Autonomous University of Barcelona, 08193, Bellaterra, Spain Received 30 January 2015; revised 14 April 2015; accepted 4 May 2015 Published online 13 May 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/bip.22669 past two calendar years by emailing the Biopolymers editorial ABSTRACT: office at [email protected]. Peptides and proteins are attractive initial leads for the rational design of bioactive molecules. Several natural INTRODUCTION cyclic peptides have recently emerged as templates for eptides constitute one of the most promising plat- drug design due to their resistance to chemical or enzy- forms for drug development due to their biocom- matic hydrolysis and high selectivity to receptors. The patibility, chemical diversity, and resemblance to proteins.1 Inspired by the protein assembly in bio- development of practical protocols that mimic the power logical systems, a large number of peptides have of nature’s strategies remains paramount for the P been designed using different amino acids and sequences, advancement of novel peptide-based drugs. The de novo while forming unique folded structures (“fold-on-binding”) design of peptide mimetics (nonpeptide molecules or and providing a broad spectrum of physiological and biolog- ical activities.2 In this regard, peptides have triggered applica- cyclic peptides) for the synthesis of linear or cyclic pep- tions that currently range from drug discovery3 to tides has enhanced the progress of therapeutics and nanomaterials;4 such as nanofibers for biomedical purposes, diverse areas of science and technology.
    [Show full text]
  • United States Patent (10) Patent No.: US 7,323,169 B2 Goldenberg Et Al
    USOO7323169B2 (12) United States Patent (10) Patent No.: US 7,323,169 B2 Goldenberg et al. (45) Date of Patent: Jan. 29, 2008 (54) SUSTAINED RELEASE FORMULATIONS 2005/0215470 A1* 9/2005 Ng et al. ...................... 514/12 (75) Inventors: Merrill S. Goldenberg, Thousand FOREIGN PATENT DOCUMENTS Oaks, CA (US); Jian Hua Gu, 3 SA 3. Thousand Oaks, CA (US) WO WO 94,08599 4f1994 WO WO 98,10649 3, 1998 (73) Assignee: Amgen Inc., Thousand Oaks, CA (US) WO WO 99,04764 A1 * 2, 1999 WO WOOO, 51643 9, 2000 (*) Notice: Subject to any disclaimer, the term of this WO WO O1/32.218 5, 2001 patent 1s listed Ojusted under 35 WO WO2004O12522 A 2, 2004 U.S.C. 154(b) by 40 days. OTHER PUBLICATIONS (21)21) AppAppl. No.: 11/114,4739 Hatano et al. Size exclusionn chromatographicgrap analysisy of polyphenol-serum albumin complexes. Phytochemistry. 2003, vol. (22) Filed: Apr. 25, 2005 63, pp. 817-823.* Naurato et al. Interaction of Tannin with Human Salivary Histatins. (65) Prior Publication Data Journal of Agricultural and Food Chemistry. May, 4, 1999, vol. 47. No. 6, pp. 2229-2234.* US 2005/0271722 A1 Dec. 8, 2005 M. Chasin, “Biodegradable Polymers for Controlled Drug Deliv ery J.O. Hollinger Editor, Biomedical Applications of Synthetic Related U.S. Application Data Biodegradable Polymers CRC, Boca Raton, Florida (1995) pp. 1-15. (60) Provisional application No. 60/565,247, filed on Apr. T. Hayashi. “Biodegradable Polympers for Biomedical Uses' Prog. 23, 2004. Polym. Sci. 19:4 (1994) pp. 663-700. Harjit Tamber et al., “Formulation Aspects of Biodegradable Poly (51) Int.
    [Show full text]
  • Role of Surfactin from Bacillus Subtilis in Protection Against Antimicrobial Peptides Produced by Bacillus Species
    Role of surfactin from Bacillus subtilis in protection against antimicrobial peptides produced by Bacillus species by Hans André Eyéghé-Bickong BSc. Honours (Biochemistry) February 2011 Dissertation approved for the degree Doctor of Philosophy (Biochemistry) in the Faculty of Science at the University of Stellenbosch Promoter: Prof. Marina Rautenbach Department of Biochemistry University of Stellenbosch ii Declaration By submitting this dissertation electronically, I declare that the entirety of the work contained therein is my own, original work, that I am the sole author thereof (save to the extent explicitly otherwise stated), that reproduction and publication thereof by Stellenbosch University will not infringe any third party rights and that I have not previously in its entirety or in part submitted it for obtaining any qualification. ……………………………………………. ………28/02/2011..…………… Hans André Eyéghé-Bickong Date Copyright©2011 Stellenbosch University All rights reserved iii Summary Antagonism of antimicrobial action represents an alternative survival strategy for cohabiting soil organisms. Under competitive conditions, our group previously showed that surfactin (Srf) produced by Bacillus subtilis acts antagonistically toward gramicidin S (GS) from a cohabiting bacillus, Aneurinibacillus migulanus, causing the loss the antimicrobial activity of GS. This antagonism appeared to be caused by inactive complex formation. This study aimed to elucidate whether the previously observed antagonism of GS activity by Srf is a general resistance mechanism that also extends to related peptides such as the tyrocidines (Trcs) and linear gramicidins (Grcs) from Bacillus aneurinolyticus. Molecular interaction between the antagonistic peptide pairs was investigated using biophysical analytical methods such as electrospray mass spectrometry (ESMS), circular dichroism (CD), fluorescence spectroscopy (FS) and nuclear magnetic resonance (NMR).
    [Show full text]
  • Molecular Analysis of Candidate Probiotic Effector Molecules of Lactobacillus Plantarum
    Molecular analysis of candidate probiotic effector molecules of Lactobacillus plantarum Daniela Maria Remus Thesis committee Promoter Prof. dr. Michiel Kleerebezem Professor of Bacterial Metagenomics Wageningen University Co-promoter Dr. Peter A. Bron Senior Scientist, NIZO food research BV, Ede Other members Prof. dr. Tjakko Abee, Wageningen University Prof. dr. Pascal Hols, University of Lovain (Lovain la Neuve), Belgium Dr. Philippe Langella, National Institute of Agricultural Research (INRA), Paris, France Prof. dr. Roland J. Siezen, Radboud University, Nijmegen This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences). Molecular analysis of candidate probiotic effector molecules of Lactobacillus plantarum Daniela Maria Remus Thesis submitted in fulfillment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. dr. M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Tuesday 09 October 2012 at 4 p.m. in the Aula. Daniela Maria Remus Molecular analysis of candidate probiotic effector molecules of Lactobacillus plantarum Ph.D. Thesis, Wageningen University, Wageningen, The Netherlands (2012) With references and summaries in English and Dutch. ISBN 978-94-6173-373-3 Summary Lactobacilli occupy diverse natural habitats, including dairy products and the mammalian gastrointestinal (GI) tract, and several Lactobacillus strains are marketed as probiotics that can interact with host cells in the GI tract by which they are proposed to beneficially influence the health status of their consumers. The discovery of probiotic effector molecules is instrumental to understand the exact modes of probiotic action, which is required for their controlled, safe, and purpose-directed application.
    [Show full text]
  • Plantaricin KW30
    The Molecular and Cellular Characterisation of the First Glycocin: Plantaricin KW30 Judith Stepper 2009 The Molecular and Cellular Characterisation of the First Glycocin: Plantaricin KW30 A thesis presented in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biochemistry at Massey University, Palmerston North, New Zealand Judith Stepper 2009 “What we know is a drop. What we don’t know is an ocean.” Isaac Newton (1643 – 1727) ABSTRACT Bacteriocins, typically secreted by Gram-positive and -negative bacteria, are ribosomally- synthesised antimicrobial peptides which inhibit the growth of competing bacteria. We have purified a 43 amino acid bacteriocin, plantaricin KW30 (PlnKW30) produced by Lactobacillus plantarum KW30, that has little amino acid sequence similarity to any other characterised bacteriocin. The gene encoding plnKW30 is in a cluster with the genes required for maturation and export of, and immunity to, the bacteriocin. This arrangement of genes is similar to the genomic context of bacteriocin genes in other lactic acid bacteria. The plnKW30 gene cluster comprises six genes encoding a glycosyltransferase, a proteolytic ABC-transporter, two putative thioredoxins, a response regulator and PlnKW30 itself. PlnKW30 was found to possess two unusual post-translational modifications: an O-glycosylated serine and an unprecedented S-glycosylation of the C-terminal cysteine. The modified serine is located on an eight residue loop that is tethered by a disulfide bridge. Both modifications have been identified as N-acetylglucosamines (GlcNAc), making PlnKW30 the first described class IV bacteriocin. A post-translational modification with S-linked GlcNAc is unprecedented in bacteriocins as well as in all genera.
    [Show full text]
  • The Bacteriostatic Diglycocylated Bacteriocin Glycocin F Targets A
    Copyright is owned by the Author of the thesis. Permission is given for a copy to be downloaded by an individual for the purpose of research and private study only. The thesis may not be reproduced elsewhere without the permission of the Author. The Bacteriostatic Diglycosylated Bacteriocin Glycocin F Targets a Sugar-Specific Transporter A thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Biochemistry at Massey University, Manawatu New Zealand Kelvin Ross Drower 2014 Dedicated to Nana and Pop Abstract The increasing prevalence of antibiotic-resistance bacteria is threatening to end the antibiotic era established following Alexander Fleming's discovery of penicillin in 1928. Over-prescription and misuse of broad-spectrum antibiotics has hastened the development and spread of antibiotic resistance. This, combined with a lack of research and development (R&D) of new antibiotics by major pharmaceutical companies, may lead to a widespread recurrence of 'incurable' bacterial diseases. However while commercial R&D of antibiotics has waned, much research has been carried out to characterise bacteriocins, ribosomally-synthesised antimicrobial polypeptides thought to be produced by virtually all prokaryotes. Although hundreds of bacteriocins have been identified and characterised, only a handful of their cognate receptors on susceptible cells have been identified. Glycocin F is a bacteriostatic diglycosylated 43-amino acid bacteriocin produced by the Gram-positive bacterium Lactobacillus plantarum KW30 that inhibits the growth of a broad range of bacteria. The mechanism of action of glycocin F is unknown, however evidence suggested that glycocin F binds to cells via a N-acetylglucosamine (GlcNAc) specific phosphoenolpyruvate:carbohydrate-phosphotransferase system (PTS) transporter, as had been shown for lactococcin A, lactococcin B and microcin E492 that target a mannose specific PTS transporter.
    [Show full text]
  • A Global Review on Short Peptides: Frontiers and Perspectives †
    molecules Review A Global Review on Short Peptides: Frontiers and Perspectives † Vasso Apostolopoulos 1 , Joanna Bojarska 2,* , Tsun-Thai Chai 3 , Sherif Elnagdy 4 , Krzysztof Kaczmarek 5 , John Matsoukas 1,6,7, Roger New 8,9, Keykavous Parang 10 , Octavio Paredes Lopez 11 , Hamideh Parhiz 12, Conrad O. Perera 13, Monica Pickholz 14,15, Milan Remko 16, Michele Saviano 17, Mariusz Skwarczynski 18, Yefeng Tang 19, Wojciech M. Wolf 2,*, Taku Yoshiya 20 , Janusz Zabrocki 5, Piotr Zielenkiewicz 21,22 , Maha AlKhazindar 4 , Vanessa Barriga 1, Konstantinos Kelaidonis 6, Elham Mousavinezhad Sarasia 9 and Istvan Toth 18,23,24 1 Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia; [email protected] (V.A.); [email protected] (J.M.); [email protected] (V.B.) 2 Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego˙ 116, 90-924 Lodz, Poland 3 Department of Chemical Science, Faculty of Science, Universiti Tunku Abdul Rahman, Kampar 31900, Malaysia; [email protected] 4 Botany and Microbiology Department, Faculty of Science, Cairo University, Gamaa St., Giza 12613, Egypt; [email protected] (S.E.); [email protected] (M.A.) 5 Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego˙ 116, 90-924 Lodz, Poland; [email protected] (K.K.); [email protected] (J.Z.) 6 NewDrug, Patras Science Park, 26500 Patras, Greece; [email protected] 7 Department of Physiology and Pharmacology,
    [Show full text]
  • Biological Function of Gramicidin: Studies on Gramicidin-Negative Mutants (Peptide Antibiotics/Sporulation/Dipicolinic Acid/Bacillus Brevis) PRANAB K
    Proc. NatS. Acad. Sci. USA Vol. 74, No. 2, pp. 780-784, February 1977 Microbiology Biological function of gramicidin: Studies on gramicidin-negative mutants (peptide antibiotics/sporulation/dipicolinic acid/Bacillus brevis) PRANAB K. MUKHERJEE AND HENRY PAULUS Department of Metabolic Regulation, Boston Biomedical Research Institute, Boston, Massachusetts 02114; and Department of Biological Chemistry, Harvard Medical School, Boston, Massachusetts 02115 Communicated by Bernard D. Davis, October 28,1976 ABSTRACT By the use of a rapid radioautographic EXPERIMENTAL PROCEDURE screening rocedure, two mutants of Bacillus brevis ATCC 8185 that have lost the ability to produce gramicidin have been iso- lated. These mutants produced normal levels of tyrocidine and Bacterial Strains. Bacillus brevis ATCC 8185, the Dubos sporulated at the same frequency as the parent strain. Their strain, was obtained from the American Type Culture Collec- spores, however, were more heat-sensitive and had a reduced tion. Strain S14 is a streptomycin-resistant derivative of B. brevis 4ipicolinic acid content. Gramicidin-producing revertants oc- ATCC 8185, isolated on a streptomycin-gradient plate without curred at a relatively high frequency among tie survivors of mutagenesis. It grows well at 0.5 mg/ml of streptomycin, but prolonged heat treatment and had also regained the ability to produce heat-resistant spores. A normal spore phenotype could growth is retarded by streptomycin at 1.0 mg/ml. Strain B81 also be restored by the addition of gramicidin to cultures of the is a rifampicin-resistant derivative of strain S14, isolated on mutant strain at the end of exponential growth. On the other rifampicin-gradient plates after mutagenesis of spores with hand, the addition of dipicolinic acid could not cure the spore ethyl methanesulfonate (11).
    [Show full text]
  • Recent Advances in Chiral Analysis of Proteins and Peptides
    separations Review Recent Advances in Chiral Analysis of Proteins and Peptides Marine Morvan 1,2,* and Ivan Mikšík 1,2,* 1 Institute of Physiology of the Czech Academy of Sciences, Vídeˇnská 1083, 142 20 Prague, Czech Republic 2 Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic * Correspondence: [email protected] (M.M.); [email protected] (I.M.) Abstract: Like many biological compounds, proteins are found primarily in their homochiral form. However, homochirality is not guaranteed throughout life. Determining their chiral proteinogenic sequence is a complex analytical challenge. This is because certain D-amino acids contained in proteins play a role in human health and disease. This is the case, for example, with D-Asp in elastin, b-amyloid and a-crystallin which, respectively, have an action on arteriosclerosis, Alzheimer’s disease and cataracts. Sequence-dependent and sequence-independent are the two strategies for detecting the presence and position of D-amino acids in proteins. These methods rely on enzymatic digestion by a site-specific enzyme and acid hydrolysis in a deuterium or tritium environment to limit the natural racemization of amino acids. In this review, chromatographic and electrophoretic techniques, such as LC, SFC, GC and CE, will be recently developed (2018–2020) for the enantioseparation of amino acids and peptides. For future work, the discovery and development of new chiral stationary phases and derivatization reagents could increase the resolution of chiral separations. Keywords: chiral separation; proteins; peptides; D-amino acids Citation: Morvan, M.; Mikšík, I. Recent Advances in Chiral Analysis of Proteins and Peptides.
    [Show full text]