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Anti-infective Drug Discovery

Dr Martin Empting

Work in the Empting lab focuses on tackling innovative and difficult-to-address anti-infective targets such as bacterial virulence regulatory systems as well as un(der)explored anti-herpesviral persitance mediators. By this, we aspire to circumvent common resistance mechanisms and to refill the dried out development pipeline.

Our research and approach

We progress our antiinfective projects through all the stages of drug discovery. Our hit-finding strategies are selected individually for the target molecule at hand. In the case of receptors and enzymes with pockets druggable with small molecules (e.g. PqsR, PqsE), we employ fragment-based methodologies and transform identified starting points (hits) into drug-like molecules (leads) by medicinal chemistry optimization. In this regard, we follow a multi-parameter optimization considering not only potency but also pharmacokinetic and safety pharmacology endpoints. Ideally, leads are optimized towards preclinical profiling candidate status in order to facilitate preclinical development.

Difficult-to-drug macromolecule-macromolecule interactions provide challenging, yet, promising and notoriously underexploited points of disease intervention. We have been successful in applying above-mentioned fragment-based hit identification to a protein-DNA interaction essential for the lifecycle of human herpesvirus 8 (Kaposi´s sarcoma herpesvirus, KSHV) mediated by the latency-associated nuclear antigen (LANA). In order to supplement and complement these small molecule-directed approaches, we also apply the phage display technology for the screening of very short macrocyclic (constrained) peptide sequences. The resulting hits are readily synthetically accessible starting points amenable to medicinal chemistry optimization towards novel drug molecules at the boarders of Lipinski´s rule of five (or just slightly beyond). In the future, we aim to combine fragment- and phage-display-based approaches to generate peptide-small molecules hybrids with the aim to explore currently untapped chemical space.

 

Team members

Research projects

Targeting bacterial Pathogenicity (Pathoblockers)

With the aim to devise novel treatment modalities and to divert from classical bactericidal or bacteriostatic antibiotics, we design and optimize synthetic molecules, which specifically block bacterial pathogenicity traits. In this regard, we address transcriptional and post-transcriptional regulators of bacterial virulence. By this means, we interfere with a multitude of virulence factors and do not interfere with bacterial viability. The overall aim of the project is to discover and advance compounds for the treatment of Pseudomonas aeruginosa infections, which is a problematic ESKAPE pathogen and the major cause of morbidity and mortality in patients with cystic fibrosis. To this end, we address to regulator systems: A) the Pseudomonas quinolone signal (PQS) quorum sensing (QS) system and B) the carbon storage regulator (Csr; also called regulator of secondary metabolites, Rsm) system.

A) QS provides a way for bacteria to communicate with each other via small diffusible signal molecules. This ability is essential for population-wide coordination of infection processes. We target the signal molecule receptor and transcriptional regulator PqsR (MvfR) by compounds acting as inverse agonists. The PQS QS system is quite unique resulting in a pathogen-specific mode-of-action, which preserves the commensal (beneficial) microbiota. By means, we successfully achieved lead status with three chemical classes of pathoblockers showing promising potency in the nanomolar range combined with a suitable pharmacokinetic and in vitro safety pharmacology profile. This project is currently in the late lead optimization stage.

B) In contrast to the PQS QS, the Csr/Rsm system is astonishingly widespread among pathogenic bacteria. Hence, this higher order regulatory system holds promise as a potential broad-spectrum pathoblocker target. We were able to identify identify natural product-derived small molecule-like hits as well as novel peptidic macrocyclic starting points for medicinal chemistry optimization. Demonstration of cellular activity mediated by blocking this post-transcriptional regulator is the next step in this project.

Targeting persistence of human herpes viruses

The latency-associated nuclear antigen (LANA) is required for latent replication and persistence of Kaposi’sarcoma-associated herpesvirus/human herpesvirus 8. LANA exerts important functions in the host cell like cell survival, transcriptional control, latent viral DNA replication, and stable episome segregation during mitosis. It acts via tethering the virus episome to the host chromatin. We aim to discover novel antiviral drugs, which to inhibit the interaction between LANA and the viral genome. By this means, we should be able to disrupt the latent replication of KSHV.

We were successful in finding the first LANA inhibitors by a fragment-based approach. The resulting optimized hit provides an ideal starting point for subsequent hit-to-lead campaigns providing evident target-binding, suitable ligand efficiencies, and favourable physicochemical properties. Further improved compounds are currently underway with a view to demonstrate antiviral activities in cell-based assays.

Publications

2020

Discovery of Novel Latency-Associated Nuclear Antigen Inhibitors as Antiviral Agents Against Kaposi's Sarcoma-Associated Herpesvirus

Kirsch P, Jakob V, Elgaher W, Walt C, Oberhausen K, Schulz T, Empting M (2020)

ACS chemical biology, 15 (2): 388-395DOI: 10.1021/acschembio.9b00845

Restriction-Free Construction of a Phage-Presented Very Short Macrocyclic Peptide Library

Jakob V, Helmsing S, Hust M, Empting M (2020)

Methods in molecular biology (Clifton, N.J.), 2070: 95-113DOI: 10.1007/978-1-4939-9853-1_6

2019

Synthesis of New Cyclomarin Derivatives and Their Biological Evaluation towards Mycobacterium Tuberculosis and Plasmodium Falciparum

Kiefer A, Bader C, Held J, Esser A, Rybniker J, Empting M, Müller R, Kazmaier U (2019)

Chem. Eur. J., 25 (37): 8894-8902DOI: 10.1002/chem.201901640

Hit evaluation of an α-helical peptide: Ala-scan, truncation and sidechain-to-sidechain macrocyclization of an RNA polymerase Inhibitor

Kamal A, Habib M, Haupenthal J, Hartmann R, Empting M (2019)

Biol. Chem., 400 (3): 333-342DOI: 10.1515/hsz-2018-0333

Fragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8

Kirsch P, Jakob V, Oberhausen K, Stein S, Cucarro I, Schulz T, Empting M (2019)

Journal of medicinal chemistry, 62 (8): 3924-3939DOI: 10.1021/acs.jmedchem.8b01827

Concepts and Core Principles of Fragment-Based Drug Design

Kirsch P, Hartman A, Hirsch A, Empting M (2019)

Molecules (Basel, Switzerland), 24 (23)DOI: 10.3390/molecules24234309

2018

The Alkylquinolone Repertoire of Pseudomonas aeruginosa is Linked to Structural Flexibility of the FabH-like 2-Heptyl-3-hydroxy-4(1H)-quinolone (PQS) Biosynthesis Enzyme PqsBC

Witzgall F, Depke T, Hoffmann M, Empting M, Brönstrup M, Müller R, Blankenfeldt W (2018)

Chembiochem : a European journal of chemical biology, 19 (14): 1531-1544DOI: 10.1002/cbic.201800153

Tackling Pseudomonas aeruginosa Virulence by a Hydroxamic Acid-Based LasB Inhibitor

Kany A, Sikandar A, Yahiaoui S, Haupenthal J, Walter I, Empting M, Köhnke J, Hartmann R (2018)

ACS chemical biology, 13 (9): 2449-2455DOI: 10.1021/acschembio.8b00257

Aspherical and Spherical InvA497-Functionalized Nanocarriers for Intracellular Delivery of Anti-Infective Agents

Castoldi A, Empting M, Rossi C, Mayr K, Dersch P, Hartmann R, Müller R, Gordon S, Lehr C (2018)

Pharm Res, 36 (1)DOI: 10.1007/s11095-018-2521-3

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

Schütz C, Empting M (2018)

Beilstein journal of organic chemistry, 14: 2627-2645DOI: 10.3762/bjoc.14.241

Generation of Semi-Synthetic Shark IgNAR Single-Domain Antibody Libraries

Grzeschik J, Könning D, Hinz S, Krah S, Schröter C, Empting M, Kolmar H, Zielonka S (2018)

Methods in molecular biology (Clifton, N.J.), 1701: 147-167DOI: 10.1007/978-1-4939-7447-4_8

2017

In-depth Profiling of MvfR-Regulated Small Molecules in Pseudomonas aeruginosa after Quorum Sensing Inhibitor Treatment

Allegretta G, Maurer C, Eberhard J, Maura D, Hartmann R, Rahme L, Empting M (2017)

Frontiers in microbiology, 8DOI: 10.3389/fmicb.2017.00924

Semi-synthetic vNAR libraries screened against therapeutic antibodies primarily deliver anti-idiotypic binders

Könning D, Rhiel L, Empting M, Grzeschik J, Sellmann C, Schröter C, Zielonka S, Dickgießer S, Pirzer T, Yanakieva D, Becker S, Kolmar H (2017)

Sci. Rep., 7 (1)DOI: 10.1038/s41598-017-10513-9

Camelid and shark single domain antibodies: structural features and therapeutic potential

Könning D, Zielonka S, Grzeschik J, Empting M, Valldorf B, Krah S, Schröter C, Sellmann C, Hock B, Kolmar H (2017)

Current opinion in structural biology, 45: 10-16DOI: 10.1016/j.sbi.2016.10.019

2016

Single-domain antibodies for biomedical applications

Krah S, Schröter C, Zielonka S, Empting M, Valldorf B, Kolmar H (2016)

Immunopharmacol. Immunotoxicol., 38 (1): 21-8DOI: 10.3109/08923973.2015.1102934

Structure-Activity Relationships of 2-Sufonylpyrimidines as Quorum-Sensing Inhibitors to Tackle Biofilm Formation and eDNA Release of Pseudomonas aeruginosa

Thomann A, Brengel C, Börger C, Kail D, Steinbach A, Empting M, Hartmann R (2016)

ChemMedChem, 11 (22): 2522-2533DOI: 10.1002/cmdc.201600419

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

Discovery of the first small-molecule CsrA-RNA interaction inhibitors using biophysical screening technologies

Maurer C, Fruth M, Empting M, Avrutina O, Hossmann J, Nadmid S, Gorges J, Herrmann J, Kazmaier U, Dersch P, Müller R, Hartmann R (2016)

Future Med. Chem., 8 (9): 931-47DOI: 10.4155/fmc-2016-0033

Application of Dual Inhibition Concept within Looped Autoregulatory Systems toward Antivirulence Agents against Pseudomonas aeruginosa Infections

Thomann A, de Mello Martins, Antonio G G, Brengel C, Empting M, Hartmann R (2016)

ACS chemical biologyDOI: 10.1021/acschembio.6b00117

2015

Engineering a Constrained Peptidic Scaffold towards Potent and Selective Furin Inhibitors

Fittler H, Depp A, Avrutina O, Dahms S, Than M, Empting M, Kolmar H (2015)

Chembiochem : a European journal of chemical biology, 16 (17): 2441-4DOI: 10.1002/cbic.201500447

Towards the evaluation in an animal disease model: Fluorinated 17β-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme

Abdelsamie A, Bey E, Gargano E, van Koppen C, Empting M, Frotscher M (2015)

European journal of medicinal chemistry, 103: 56-68DOI: 10.1016/j.ejmech.2015.08.030

Catechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD

Allegretta G, Weidel E, Empting M, Hartmann R (2015)

European journal of medicinal chemistry, 90: 351-9DOI: 10.1016/j.ejmech.2014.11.055

Exploring the chemical space of ureidothiophene-2-carboxylic acids as inhibitors of the quorum sensing enzyme PqsD from Pseudomonas aeruginosa

Sahner J, Empting M, Kamal A, Weidel E, Groh M, Börger C, Hartmann R (2015)

European journal of medicinal chemistry, 96: 14-21DOI: 10.1016/j.ejmech.2015.04.007

2014

Composing compound libraries for hit discovery--rationality-driven preselection or random choice by structural diversity?

Weidel E, Negri M, Empting M, Hinsberger S, Hartmann R (2014)

Future medicinal chemistry, 6 (18): 2057-72DOI: 10.4155/fmc.14.142

Potent inhibitors of human matriptase-1 based on the scaffold of sunflower trypsin inhibitor

Fittler H, Avrutina O, Empting M, Kolmar H (2014)

Journal of peptide science : an official publication of the European Peptide Society, 20 (6): 415-20DOI: 10.1002/psc.2629

Design and synthesis of a library of lead-like 2,4-bisheterocyclic substituted thiophenes as selective Dyrk/Clk inhibitors

Schmitt C, Kail D, Mariano M, Empting M, Weber N, Paul T, Hartmann R, Engel M (2014)

PLoS ONE, 9 (3)DOI: 10.1371/journal.pone.0087851

Inhibition of 17β-HSD1: SAR of bicyclic substituted hydroxyphenylmethanones and discovery of new potent inhibitors with thioether linker

Abdelsamie A, Bey E, Hanke N, Empting M, Hartmann R, Frotscher M (2014)

European journal of medicinal chemistry, 82: 394-406DOI: 10.1016/j.ejmech.2014.05.074

From in vitro to in cellulo: structure-activity relationship of (2-nitrophenyl)methanol derivatives as inhibitors of PqsD in Pseudomonas aeruginosa

Storz M, Allegretta G, Kirsch B, Empting M, Hartmann R (2014)

Organic & biomolecular chemistry, 12 (32): 6094-104DOI: 10.1039/c4ob00707g

2013

Combinatorial tuning of peptidic drug candidates: high-affinity matriptase inhibitors through incremental structure-guided optimization

Fittler H, Avrutina O, Glotzbach B, Empting M, Kolmar H (2013)

Org. Biomol. Chem., 11 (11): 1848-57DOI: 10.1039/c3ob27469a

PHIP-label: parahydrogen-induced polarization in propargylglycine-containing synthetic oligopeptides

Körner M, Sauer G, Heil A, Nasu D, Empting M, Tietze D, Voigt S, Weidler H, Gutmann T, Avrutina O, …, Ratajczyk T, Buntkowsky G (2013)

Chemical communications (Cambridge, England), 49 (71): 7839-41DOI: 10.1039/c3cc43978j

2012

From pico to nano: biofunctionalization of cube-octameric silsesquioxanes by peptides and miniproteins

Fabritz S, Hörner S, Könning D, Empting M, Reinwarth M, Dietz C, Glotzbach B, Frauendorf H, Kolmar H, Avrutina O (2012)

Org. Biomol. Chem., 10 (31): 6287-93DOI: 10.1039/c2ob25728a

Between two worlds: a comparative study on in vitro and in silico inhibition of trypsin and matriptase by redox-stable SFTI-1 variants at near physiological pH

Avrutina O, Fittler H, Glotzbach B, Kolmar H, Empting M (2012)

Org. Biomol. Chem., 10 (38): 7753-62DOI: 10.1039/c2ob26162f

Braces for the peptide backbone: insights into structure-activity relationships of protease inhibitor mimics with locked amide conformations

Tischler M, Nasu D, Empting M, Schmelz S, Heinz D, Rottmann P, Kolmar H, Buntkowsky G, Tietze D, Avrutina O (2012)

Angewandte Chemie (International ed. in English), 51 (15): 3708-12DOI: 10.1002/anie.201108983

2011

'Triazole bridge': disulfide-bond replacement by ruthenium-catalyzed formation of 1,5-disubstituted 1,2,3-triazoles

Empting M, Avrutina O, Meusinger R, Fabritz S, Reinwarth M, Biesalski M, Voigt S, Buntkowsky G, Kolmar H (2011)

Angewandte Chemie (International ed. in English), 50 (22): 5207-11DOI: 10.1002/anie.201008142

2010

Towards click bioconjugations on cube-octameric silsesquioxane scaffolds

Fabritz S, Heyl D, Bagutski V, Empting M, Rikowski E, Frauendorf H, Balog I, Fessner W, Schneider J, Avrutina O, Kolmar H (2010)

Org. Biomol. Chem., 8 (9): 2212-8DOI: 10.1039/b923393h

2009

Application of copper(I) catalyzed azide-alkyne 3+2 cycloaddition to the synthesis of template-assembled multivalent peptide conjugates

Avrutina O, Empting M, Fabritz S, Daneschdar M, Frauendorf H, Diederichsen U, Kolmar H (2009)

Org. Biomol. Chem., 7 (20): 4177-85DOI: 10.1039/b908261a

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