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Chemical Biology of Carbohydrates

Prof Dr Alexander Titz

Complex carbohydrates play a vital role in biological recognition processes that are represented by the presence of dense glycoconjugate layers on cells known as the glycocalyx. Despite their importance, the study of carbohydrates suffers from limited methods for their synthesis and analysis contrary to nucleic acids or proteins. The lab of Dr. Alexander Titz focuses on the development of novel glycomimetics to fight mechanisms of chronic bacterial infections such as biofilm formation of P. aeruginosa.

Our research and approach

Treatment of chronic infections: disrupting lectin-mediated biofilms

Many human pathogens can establish chronic infections with the help of a biofilm mode of life. As a protective shield, the matrix of the biofilm renders antibiotics ineffective and secures survival of the embedded pathogen. Novel ways for treatment address disintegration of such biofilms and thus restore activity of antibiotics. Frequently, the architecture of biofilms is maintained by carbohydrates and so-called lectins, recognizing and cross-linking carbohydrate motifs of the glycocalyx, both on human cells and pathogens. The inhibition of such structural components leads to the disruption of a biofilm and thereby allows treatment of the infection. Pseudomonas aeruginosa is an important pathogen in hospital-acquired infections and for cystic fibrosis patients. This Gram-negative bacterium can establish chronic infections in various tissues through assembly into protective biofilms. One focus of our research is two Pseudomonas aeruginosa lectins, which are crucial elements of the biofilm architecture.

The group of Dr. Alexander Titz aims at the development of antibacterial drugs using a combination of medicinal chemistry, biochemistry and microbiological methods. Recently, a competitive binding assay was developed for the in vitro evaluation of inhibitors of the Pseudomonas lectins. In collaboration with other groups at HIPS and the HZI, potent molecules obtained by the group are then further evaluated in biofilm and infection models. Such compounds may ultimately lead to successful treatment of chronic infections without evoking resistances among the pathogens.
 

Team members

Eike Siebs

Eike Siebs

PhD Student

Eva Zahorska

Eva Zahorska

PhD Student

Joscha Meiers

Joscha Meiers

PhD Student

Olga Metelkina

Olga Metelkina

PhD Student

Varvara Verkhova

Varvara Verkhova

PhD Student

Dirk Hauck

Dirk Hauck

Technical Assistant

Lisa Marie Denig

Lisa Marie Denig

Technical Assistant

Research projects

Sweetbullets (Joscha Meiers, Olga Metelkina, Varvara Verkhova and Eva Zahorska)

https://cordis.europa.eu/project/rcn/206491/factsheet/en _blank

Development of non-carbohydrate glycomimetics (Eike Siebs)

https://gepris.dfg.de/gepris/projekt/390973730 _blank

Publications

2020

Expression, Purification, and Functional Characterization of Tectonin 2 from Laccaria bicolor: A Six-Bladed Beta-Propeller Lectin Specific for O-Methylated Glycans

Wohlschlager T, Titz A, Künzler M, Varrot A (2020)

Methods Mol Biol, 2132: 669-682DOI: 10.1007/978-1-0716-0430-4_58

2019

Lectin antagonists in infection, immunity, and inflammation

Meiers J, Siebs E, Zahorska E, Titz A (2019)

Current opinion in chemical biology, 53: 51-67DOI: 10.1016/j.cbpa.2019.07.005

Anti-biofilm Agents against Pseudomonas aeruginosa: A Structure-Activity Relationship Study of C-Glycosidic LecB Inhibitors

Sommer R, Rox K, Wagner S, Hauck D, Henrikus S, Newsad S, Arnold T, Ryckmans T, Brönstrup M, Imberty A, …, Hartmann R, Titz A (2019)

Journal of medicinal chemistry, 62 (20): 9201-9216DOI: 10.1021/acs.jmedchem.9b01120

Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis

Siebert D, Sommer R, Pogorevc D, Hoffmann M, Wenzel S, Müller R, Titz A (2019)

Beilstein journal of organic chemistry, 15: 2922-2929DOI: 10.3762/bjoc.15.286

Induction of rare conformation of oligosaccharide by binding to calcium-dependent bacterial lectin: X-ray crystallography and modelling study

Lepsik M, Sommer R, Kuhaudomlarp S, Lelimousin M, Paci E, Varrot A, Titz A, Imberty A (2019)

European journal of medicinal chemistry, 177: 212-220DOI: 10.1016/j.ejmech.2019.05.049

2018

Bivalent LecA inhibitors targeting Pseudomonas aeruginosa LecA

Zahorska E, Minervini S, Kuhaudomlarp S, Imberty A, Titz A (2018)

Patent (EP19306432.6)

N-Acetylmuramic Acid (MurNAc) Auxotrophy of the Oral Pathogen Tannerella forsythia: Characterization of a MurNAc Kinase and Analysis of Its Role in Cell Wall Metabolism

Hottmann I, Mayer V, Tomek M, Friedrich V, Calvert M, Titz A, Schäffer C, Mayer C (2018)

Frontiers in microbiology, 9DOI: 10.3389/fmicb.2018.00019

Crystal Structures of Fungal Tectonin in Complex with O-Methylated Glycans Suggest Key Role in Innate Immune Defense

Sommer R, Makshakova O, Wohlschlager T, Hutin S, Marsh M, Titz A, Künzler M, Varrot A (2018)

Structure (London, England : 1993), 26 (3): 391-402DOI: 10.1016/j.str.2018.01.003

Glycomimetic, Orally Bioavailable LecB Inhibitors Block Biofilm Formation of Pseudomonas aeruginosa

Sommer R, Wagner S, Rox K, Varrot A, Hauck D, Wamhoff E, Schreiber J, Ryckmans T, Brunner T, Rademacher C, …, Imberty A, Titz A (2018)

Journal of the American Chemical Society, 140 (7): 2537-2545DOI: 10.1021/jacs.7b11133

Virtual Screening Against Carbohydrate-Binding Proteins: Evaluation and Application to Bacterial Burkholderia ambifaria Lectin

Dingjan T, Gillon É, Imberty A, Pérez S, Titz A, Ramsland P, Yuriev E (2018)

Journal of chemical information and modeling, 58 (9): 1976-1989DOI: 10.1021/acs.jcim.8b00185

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

Calvert M, Jumde V, Titz A (2018)

Beilstein journal of organic chemistry, 14: 2607-2617DOI: 10.3762/bjoc.14.239

2017

An efficient synthesis of 1,6-anhydro-N-acetylmuramic acid from N-acetylglucosamine

Calvert M, Mayer C, Titz A (2017)

Beilstein journal of organic chemistry, 13: 2631-2636DOI: 10.3762/bjoc.13.261

Covalent Lectin Inhibition and Application in Bacterial Biofilm Imaging

Wagner S, Hauck D, Hoffmann M, Sommer R, Joachim I, Müller R, Imberty A, Varrot A, Titz A (2017)

Angewandte Chemie (International ed. in English), 56 (52): 16559-16564DOI: 10.1002/anie.201709368

Photorhabdus luminescens lectin A (PllA): A new probe for detecting α-galactoside-terminating glycoconjugates

Beshr G, Sikandar A, Jemiller E, Klymiuk N, Hauck D, Wagner S, Wolf E, Koehnke J, Titz A (2017)

J Biol Chem, 292 (48): 19935-19951DOI: 10.1074/jbc.M117.812792

Ciprofloxacin-loaded lipid-core nanocapsules as mucus penetrating drug delivery system intended for the treatment of bacterial infections in cystic fibrosis

Torge A, Wagner S, Chaves P, Oliveira E, Guterres S, Pohlmann A, Titz A, Schneider M, Beck R (2017)

Int J Pharm, 527 (1-2): 92-102DOI: 10.1016/j.ijpharm.2017.05.013

Efficient Two Step β-Glycoside Synthesis from N-Acetyl d-Glucosamine: Scope and Limitations of Copper(II) Triflate-Catalyzed Glycosylation

Sommer R, Hauck D, Titz A (2017)

ChemistrySelect, 2 (15)DOI: 10.1002/slct.201700161

Photoswitchable Janus glycodendrimer micelles as multivalent inhibitors of LecA and LecB from Pseudomonas aeruginosa

Hu Y, Beshr G, Garvey C, Tabor R, Titz A, Wilkinson B (2017)

Colloids and surfaces. B, Biointerfaces, 159: 605-612DOI: 10.1016/j.colsurfb.2017.08.016

2016

Novel Strategies for the Treatment of Pseudomonas aeruginosa Infections

Wagner S, Sommer R, Hinsberger S, Lu C, Hartmann R, Empting M, Titz A (2016)

Journal of medicinal chemistry, 59 (13): 5929-69DOI: 10.1021/acs.jmedchem.5b01698

Inhibitors of Pseudomonas aeruginosa LecB

Sommer R, Titz A (2016)

Patent (WO2016/151066 A1)

O-Alkylated heavy atom carbohydrate probes for protein X-ray crystallography: Studies towards the synthesis of methyl 2-O-methyl-L-selenofucopyranoside

Sommer R, Hauck D, Varrot A, Imberty A, Künzler M, Titz A (2016)

Beilstein journal of organic chemistry, 12: 2828-2833DOI: 10.3762/bjoc.12.282

Development of a competitive binding assay for the Burkholderia cenocepacia lectin BC2L-A and structure activity relationship of natural and synthetic inhibitors

Beshr G, Sommer R, Hauck D, Siebert D, Hofmann A, Imberty A, Titz A (2016)

Med Chem Commun, 7 (3): 519-530DOI: 10.1039/C5MD00557D

Development and optimization of a competitive binding assay for the galactophilic low affinity lectin LecA from Pseudomonas aeruginosa

Joachim I, Rikker S, Hauck D, Ponader D, Boden S, Sommer R, Hartmann L, Titz A (2016)

Org. Biomol. Chem., 14 (33): 7933-48DOI: 10.1039/c6ob01313a

The virulence factor LecB varies in clinical isolates: consequences for ligand binding and drug discovery

Sommer R, Wagner S, Varrot A, Nycholat C, Khaledi A, Häussler S, Paulson J, Imberty A, Titz A (2016)

Chem Sci, 7 (8): 4990-5001DOI: 10.1039/c6sc00696e

2015

Bisecting Galactose as a Feature of N-Glycans of Wild-type and Mutant Caenorhabditis elegans

Yan S, Brecker L, Jin C, Titz A, Dragosits M, Karlsson N, Jantsch V, Wilson I, Paschinger K (2015)

Mol Cell Proteomics, 14 (8): 2111-25DOI: 10.1074/mcp.M115.049817

Cinnamide Derivatives of d-Mannose as Inhibitors of the Bacterial Virulence Factor LecB from Pseudomonas aeruginosa

Sommer R, Hauck D, Varrot A, Wagner S, Audfray A, Prestel A, Möller H, Imberty A, Titz A (2015)

ChemistryOpen, 4 (6): 756-67DOI: 10.1002/open.201500162

Parasite Glycobiology: A Bittersweet Symphony

Rodrigues J, Acosta-Serrano A, Aebi M, Ferguson M, Routier F, Schiller I, Soares S, Spencer D, Titz A, Wilson I, Izquierdo L (2015)

PLoS Pathog., 11 (11)DOI: 10.1371/journal.ppat.1005169

Synthesis of mannoheptose derivatives and their evaluation as inhibitors of the lectin LecB from the opportunistic pathogen Pseudomonas aeruginosa

Hofmann A, Sommer R, Hauck D, Stifel J, Göttker-Schnetmann I, Titz A (2015)

Carbohydrate research, 412: 34-42DOI: 10.1016/j.carres.2015.04.010

2014

Methylated glycans as conserved targets of animal and fungal innate defense

Wohlschlager T, Butschi A, Grassi P, Sutov G, Gauss R, Hauck D, Schmieder S, Knobel M, Titz A, Dell A, …, Aebi M, Künzler M (2014)

Proceedings of the National Academy of Sciences of the United States of America, 111 (27): 2787-96DOI: 10.1073/pnas.1401176111

A biophysical study with carbohydrate derivatives explains the molecular basis of monosaccharide selectivity of the Pseudomonas aeruginosa lectin LecB

Sommer R, Exner T, Titz A (2014)

PLoS ONE, 9 (11)DOI: 10.1371/journal.pone.0112822

Amphiphilic cationic β(3R3)-peptides: membrane active peptidomimetics and their potential as antimicrobial agents

Mosca S, Keller J, Azzouz N, Wagner S, Titz A, Seeberger P, Brezesinski G, Hartmann L (2014)

Biomacromolecules, 15 (5): 1687-95DOI: 10.1021/bm500101w

2013

Glycomimetics as Pseudomonas aeruginosa lectin inhibitors

Titz A (2013)

Patent (WO2013152848A1)

Biofilme Neue Forschungsansätze zur Therapie bakterieller Infektionskrankheiten

Titz A (2013)

GIT Labor-Fachzeitschrift (2): 120-121

Discovery of two classes of potent glycomimetic inhibitors of Pseudomonas aeruginosa LecB with distinct binding modes

Hauck D, Joachim I, Frommeyer B, Varrot A, Philipp B, Möller H, Imberty A, Exner T, Titz A (2013)

ACS chemical biology, 8 (8): 1775-84DOI: 10.1021/cb400371r

New approaches to control infections: anti-biofilm strategies against gram-negative bacteria

Sommer R, Joachim I, Wagner S, Titz A (2013)

Chimia (Aarau), 67 (4): 286-90DOI: 10.2533/chimia.2013.286

2012

Conformational Constraints: Nature Does It Best with Sialyl Lewis x

Titz A, Marra A, Cutting B, Smieško M, Papandreou G, Dondoni A, Ernst B (2012)

Eur. J. Org. Chem., 2012 (28)DOI: 10.1002/ejoc.201200744

2010

Core beta-galactosyltransferase and uses thereof

Titz A, Butschi A, Aebi M, Wilson I, Hengartner M, Künzler M (2010)

Patent (WO2010/136209A1)

Caenorhabditis elegans N-glycan core beta-galactoside confers sensitivity towards nematotoxic fungal galectin CGL2

Butschi A, Titz A, Wälti M, Olieric V, Paschinger K, Nöbauer K, Guo X, Seeberger P, Wilson I, Aebi M, Hengartner M, Künzler M (2010)

PLoS Pathog., 6 (1)DOI: 10.1371/journal.ppat.1000717

Probing the carbohydrate recognition domain of E-selectin: the importance of the acid orientation in sLex mimetics

Titz A, Patton J, Smiesko M, Radic Z, Schwardt O, Magnani J, Ernst B (2010)

Bioorg Med Chem, 18 (1): 19-27DOI: 10.1016/j.bmc.2009.11.024

2009

Molecular basis for galactosylation of core fucose residues in invertebrates: identification of caenorhabditis elegans N-glycan core alpha1,6-fucoside beta1,4-galactosyltransferase GALT-1 as a member of a novel glycosyltransferase family

Titz A, Butschi A, Henrissat B, Fan Y, Hennet T, Razzazi-Fazeli E, Hengartner M, Wilson I, Künzler M, Aebi M (2009)

J Biol Chem, 284 (52): 36223-33DOI: 10.1074/jbc.M109.058354

2008

Is adamantane a suitable substituent to pre-organize the acid orientation in E-selectin antagonists?

Titz A, Patton J, Alker A, Porro M, Schwardt O, Hennig M, Francotte E, Magnani J, Ernst B (2008)

Bioorg Med Chem, 16 (2): 1046-56DOI: 10.1016/j.bmc.2007.07.025

2007

Mimetics of Sialyl Lewis<sup>x</sup>: The Pre-Organization of the Carboxylic Acid is Essential for Binding to Selectins

Titz A, Ernst B (2007)

CHIMIA, 61 (4): 194-197DOI: 10.2533/chimia.2007.194

2006

A safe and convenient method for the preparation of triflyl azide, and its use in diazo transfer reactions to primary amines

Titz A, Radic Z, Schwardt O, Ernst B (2006)

Tetrahedron Lett., 47 (14)DOI: 10.1016/j.tetlet.2006.01.157

Complexation of copper(II)-Chelidamate: A multifrequency-pulsed electron paramagnetic resonance and electron nuclear double resonance analysis

Ramic E, Eichel R, Dinse K, Titz A, Schmidt B (2006)

J. Phys. Chem. B, 110 (41): 20655-63DOI: 10.1021/jp061940u

2004

Electrochemical synthesis of dimerizing and nondimerizing orthoquinone monoketals

Deffieux D, Fabre I, Titz A, Léger J, Quideau S (2004)

The Journal of organic chemistry, 69 (25): 8731-8DOI: 10.1021/jo048677i

Copper dipicolinates as peptidomimetic ligands for the Src SH2 domain

Schmidt B, Jiricek J, Titz A, Ye G, Parang K (2004)

Bioorg Med Chem Lett, 14 (16): 4203-6DOI: 10.1016/j.bmcl.2004.06.018

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