Center for Molecular Medicine Cologne

Rybniker, Jan - CAP 08

Comprehensive host-cell based antibiotic drug discovery

Introduction

The past decade has seen a growing number of bacterial pathogens that are resistant to first and second line antibiotics, which increasingly concerns health care professionals throughout the world. In addition to clinical interventions such as prevention and resistance tracking the discovery of antibiotics with novel mechanism of action is a crucial measure to slow down the constant occurrence of drug resistant bacteria.
However, antibiotic development has steadily decreased in the past three decades. It is believed that novel screening methods and platforms are needed to generate a sufficient amount of lead molecules that will fill the gap of approved substances against a whole range of Gram-negative and Gram-positive pathogens. Structural limitations and the current lack of diversity in screening libraries asks for alternative approaches such as anti-virulence drug screens, novel phenotypic screening assays and the development of host-directed therapies.

A comprehensive antibiotic screening platform, combining several of these aspects, has the great potential of generating a substantial amount of lead compounds with diverse mechanisms of action, needed for the control of antibiotic drug resistance.

We have recently developed such a screening platform for the major human pathogen Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. Control of the current tuberculosis pandemic is threatened due to increasing multidrug resistance and the lack of novel substances active against this pathogen.

Our comprehensive drug screening approach is based on virulence factor driven host cell-lysis. Proof of concept studies identified novel Mtb-specific antibiotics as well as anti-virulence drugs targeting the ESX-1 secretion system, a major mycobacterial virulence factor. Within a DZIF/CMMC funded project we continuously test novel substances derived from small molecule or natural product libraries. We are currently extending our innovative screening method to highly drug-resistant Gram-negative bacteria.

  1. Rybniker J, Vocat A, Sala C, Busso P, Pojer F, Benjak A, Cole ST. Lansoprazole is an antituberculous prodrug targeting cytochrome bc1. Nat Commun. 2015;6:7659
  2. Wassermann R, Gulen MF, Sala C, Perin SG, Lou Y, Rybniker J, Schmid-Burgk JL, Schmidt T, Hornung V, Cole ST, Ablasser A. Mycobacterium tuberculosis differentially activates cgas- and inflammasome-dependent intracellular immune responses through esx-1. Cell Host Microbe. 2015;17:799-81
  3. Rybniker J, Chen JM, Sala C, Hartkoorn RC, Vocat A, Benjak A, Boy-Rottger S, Zhang M, Szekely R, Greff Z, Orfi L, Szabadkai I, Pato J, Keri G, Cole ST. Anticytolytic screen identifies inhibitors of mycobacterial virulence protein secretion. Cell Host Microbe. 2014;16:538-548
  4. Lechartier B, Rybniker J, Zumla A, Cole ST. Tuberculosis drug discovery in the post-post-genomic era. EMBO Mol Med. 2014;6:158-168 (shared first authorship)
  5. Rybniker J, Pojer F, Marienhagen J, Kolly GS, Chen JM, van Gumpel E, Hartmann P, Cole ST. The cysteine desulfurase iscs of mycobacterium tuberculosis is involved in iron-sulfur cluster biogenesis and oxidative stress defence. Biochem J. 2014;459:467-478
  6. Chen JM, Zhang M, Rybniker J, Boy-Rottger S, Dhar N, Pojer F, Cole ST. Mycobacterium tuberculosis espb binds phospholipids and mediates esxa-independent virulence. Mol Microbiol. 2013;89:1154-1166
  7. Rybniker J, Nowag A, Janicki H, Demant K, Hartmann P, Buning H. Incorporation of antigens into viral capsids augments immunogenicity of adeno-associated virus vector-based vaccines. J Virol. 2012;86:13800-13804
  8. Rybniker J, Krumbach K, van Gumpel E, Plum G, Eggeling L, Hartmann P. The cytotoxic early protein 77 of mycobacteriophage l5 interacts with msmeg_3532, an l-serine dehydratase of mycobacterium smegmatis. J Basic Microbiol. 2011;51:515-522
  • Augustin M, Schommers P, Suarez I, Koehler P, Gruell H, Klein F, Maurer C, Langerbeins P, Priesner V, Schmidt-Hellerau K, Malin JJ, Stecher M, Jung N, Wiesmuller G, Meissner A, Zweigner J, Langebartels G, Kolibay F, Suarez V, Burst V, Valentin P, Schedler D, Cornely OA, Hallek M, Fatkenheuer G, Rybniker J, and Lehmann C (2020). Rapid response infrastructure for pandemic preparedness in a tertiary care hospital: lessons learned from the COVID-19 outbreak in Cologne, Germany, February to March 2020. Euro Surveill 25.
  • Bacher P, Rosati E, Esser D, Martini GR, Saggau C, Schiminsky E, Dargvainiene J, Schroder I, Wieters I, Khodamoradi Y, Eberhardt F, Vehreschild M, Neb H, Sonntagbauer M, Conrad C, Tran F, Rosenstiel P, Markewitz R, Wandinger KP, Augustin M, Rybniker J, Kochanek M, Leypoldt F, Cornely OA, Koehler P, Franke A, and Scheffold A (2020). Low-Avidity CD4(+) T Cell Responses to SARS-CoV-2 in Unexposed Individuals and Humans with Severe COVID-19. Immunity 53, 1258-71 e5.
  • Bernardes JP, Mishra N, Tran F, Bahmer T, Best L, Blase JI, Bordoni D, Franzenburg J, Geisen U, Josephs-Spaulding J, Kohler P, Kunstner A, Rosati E, Aschenbrenner AC, Bacher P, Baran N, Boysen T, Brandt B, Bruse N, Dorr J, Drager A, Elke G, Ellinghaus D, Fischer J, Forster M, Franke A, Franzenburg S, Frey N, Friedrichs A, Fuss J, Gluck A, Hamm J, Hinrichsen F, Hoeppner MP, Imm S, Junker R, Kaiser S, Kan YH, Knoll R, Lange C, Laue G, Lier C, Lindner M, Marinos G, Markewitz R, Nattermann J, Noth R, Pickkers P, Rabe KF, Renz A, Rocken C, Rupp J, Schaffarzyk A, Scheffold A, Schulte-Schrepping J, Schunk D, Skowasch D, Ulas T, Wandinger KP, Wittig M, Zimmermann J, Busch H, Hoyer BF, Kaleta C, Heyckendorf J, Kox M, Rybniker J, Schreiber S, Schultze JL, Rosenstiel P, Network HCALB, and Deutsche C-OI (2020). Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19. Immunity 53, 1296-314 e9.
  • Di Cristanziano V, Meyer-Schwickerath C, Eberhardt KA, Rybniker J, Heger E, Knops E, Hallek M, Klein F, Holtick U, and Jung N (2020). Detection of SARS-CoV-2 viremia before onset of COVID-19 symptoms in an allo-transplanted patient with acute leukemia. Bone marrow transplantation 10.1038/s41409-020-01059-y.
  • Eberhardt KA, Meyer-Schwickerath C, Heger E, Knops E, Lehmann C, Rybniker J, Schommers P, Eichenauer DA, Kurth F, Ramharter M, Kaiser R, Holtick U, Klein F, Jung N, and Di Cristanziano V (2020). RNAemia Corresponds to Disease Severity and Antibody Response in Hospitalized COVID-19 Patients. Viruses 12.
  • Gries R, Sala C, and Rybniker J (2020). Host-Directed Therapies and Anti-Virulence Compounds to Address Anti-Microbial Resistant Tuberculosis Infection. Appl Sci-Basel 10.
  • Holscher C, Grab J, Holscher A, Muller AL, Schafer SC, and Rybniker J (2020). Chemical p38 MAP kinase inhibition constrains tissue inflammation and improves antibiotic activity in Mycobacterium tuberculosis-infected mice. Sci Rep 10, 13629.
  • Hos NJ, Fischer J, Hos D, Hejazi Z, Calabrese C, Ganesan R, Murthy AMV, Rybniker J, Kumar S, Kronke M, and Robinson N (2020). TRIM21 Is Targeted for Chaperone-Mediated Autophagy during Salmonella Typhimurium Infection. J Immunol 205, 2456-67.
  • Malin JJ, Suarez I, Priesner V, Fatkenheuer G, and Rybniker J (2020b). Remdesivir against COVID-19 and Other Viral Diseases. Clinical microbiology reviews 34.
  • Rybniker J, and Fatkenheuer G (2020). Importance of precise data on SARS-CoV-2 transmission dynamics control. Lancet Infect Dis 10.1016/S1473-3099(20)30359-5.
  • Suarez I, Gruell H, Heyckendorf J, Funger S, Lichtenstein T, Jung N, Lehmann C, Unnewehr M, Fatkenheuer G, Lange C, and Rybniker J (2020a). Intensified adjunctive corticosteroid therapy for CNS tuberculomas. Infection 48, 289-93.
  • von Amburen J, Schreiber F, Fischer J, Winter S, van Gumpel E, Simonis A, and Rybniker J (2020). Comprehensive Host Cell-Based Screening Assays for Identification of Anti-Virulence Drugs Targeting Pseudomonas aeruginosa and Salmonella Typhimurium. Microorganisms 8.
PD Dr. Dr. Jan Rybniker CMMC Cologne
PD Dr. Dr. Jan Rybniker

Center for Molecular Medicine Cologne | Clinic I of Internal Medicine | CMMC Research Building

CMMC - PI - CAP 8

+49 221 478 89611

+49 221 478 5915

Center for Molecular Medicine Cologne | Clinic I of Internal Medicine | CMMC Research Building

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50931 Cologne

https://innere1.uk-koeln.de/forschung/arbeitsgruppen-labore/translational-research-unit-infectious-diseases/ag-bacterial-pathogenesis-and-antibiotic-drug-discovery-en/

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Curriculum Vitae (CV)

Publications - Jan Rybniker

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