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.
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
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
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
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)
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
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
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
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
Drossler, L., Lehmann, C., Topelt, K., Nierhoff, D., Vehreschild, J.J., Rybniker, J., Hallek, M., Fischer, J., Stormberg, V., Fatkenheuer, G., Wieland, U., and Jung, N. (2019). HBsAg-negative/anti-HBc-positive patients treated with rituximab: prophylaxis or monitoring to prevent hepatitis B reactivation? Infection 47, 293-300.
Fischer, J., Gutierrez, S., Ganesan, R., Calabrese, C., Ranjan, R., Cildir, G., Judith Hos, N., Rybniker, J., Wolke, M., Fries, J.W.U., Tergaonkar, V., Plum, G., Antebi, A., and Robinson, N. (2019). Leptin signaling impairs macrophage defenses against Salmonella Typhimurium. Proc Natl Acad Sci U S A 116, 16551-60.
Grab, J., and Rybniker, J. (2019). The Expanding Role of p38 Mitogen-Activated Protein Kinase in Programmed Host Cell Death. Microbiol Insights 12, 1178636119864594.
Grab, J., Suarez, I., van Gumpel, E., Winter, S., Schreiber, F., Esser, A., Holscher, C., Fritsch, M., Herb, M., Schramm, M., Wachsmuth, L., Pallasch, C., Pasparakis, M., Kashkar, H., and Rybniker, J. (2019). Corticosteroids inhibit Mycobacterium tuberculosis-induced necrotic host cell death by abrogating mitochondrial membrane permeability transition. Nat Commun 10, 688.
Hohmann, C., Michels, G., Schmidt, M., Pfister, R., Mader, N., Ohler, M., Blanke, L., Jazmati, N., Lehmann, C., Rybniker, J., Funger, S.M., Fatkenheuer, G., and Jung, N. (2019). Diagnostic challenges in infective endocarditis: is PET/CT the solution? Infection 47, 579-87.
Kiefer, A., Bader, C.D., Held, J., Esser, A., Rybniker, J., Empting, M., Muller, R., and Kazmaier, U. (2019). Synthesis of New Cyclomarin Derivatives and Their Biological Evaluation towards Mycobacterium Tuberculosis and Plasmodium Falciparum. Chemistry 25, 8894-902.
Malin, J.J., Winter, S., van Gumpel, E., Plum, G., and Rybniker, J. (2019). Extremely low hit rate in a diverse chemical drug screen targeting Mycobacterium abscessus. Antimicrob Agents Chemother10.1128/AAC.01008-19.
Rybniker, J., Kohl, T.A., Barilar, I., and Niemann, S. (2019). No Evidence for Acquired Mutations Associated with Cytochrome bc 1 Inhibitor Resistance in 13,559 Clinical Mycobacterium tuberculosis Complex Isolates. Antimicrob Agents Chemother 63.
Steinbach, A., Cornely, O.A., Wisplinghoff, H., Schauss, A.C., Vehreschild, J.J., Rybniker, J., Hamprecht, A., Richter, A., Bacher, P., Scheffold, A., and Koehler, P. (2019). Mould-reactive T cells for the diagnosis of invasive mould infection-A prospective study. Mycoses 62, 562-9.
Augustin M, Horn C, Koch J, Sandaradura de Silva U, Platten M, Nierhoff D, Suarez I, Chon SH, Rybniker J, and Lehmann C (2018). Tracking Tregs: Translocation of CD49b/LAG-3(+) Type 1 T Regulatory Cells to the Gut-Associated Lymphoid Tissue of HIV(+) Patients. AIDS Res Hum Retroviruses10.1089/AID.2018.0052.
Kasper, P., Putz, K., Funger, S., Suarez, I., Jung, N., Alakus, H., Bruns, C., and Rybniker, J. (2018). Postoperative granulomatous peritonitis mimicking abdominal tuberculosis. Clin Case Rep 6, 1810-4.
Schiller, J., Klein, S., Engels, M., Buttner, R., Rybniker, J., Fatkenheuer, G., Scheid, C., Wybranski, C., Quaas, A., Reinhardt, H.C., and Flumann, R. (2018). Case Report: A Cryptosporidium infection in a patient with relapsed T-lymphoblastic lymphoma undergoing allogeneic stem cell transplantation. Eur J Haematol 100, 383-5.
Scholten, M., Suarez, I., Platten, M., Kummerle, T., Jung, N., Wyen, C., Ernst, A., Horn, C., Burst, V., Suarez, V., Rybniker, J., Fatkenheuer, G., and Lehmann, C. (2018). To prescribe, or not to prescribe: decision making in HIV-1 post-exposure prophylaxis. HIV Med 19, 645-53.
Godel, P., Fischer, J., Scheid, C., Gathof, B.S., Wolf, J., and Rybniker, J. (2017). Familial acquired thrombotic thrombocytopenic purpura in siblings - no immunogenetic link with associated human leucocyte antigens. Eur J Haematol 98, 311-3.
Herrmann, J., Rybniker, J., and Muller, R. (2017). Novel and revisited approaches in antituberculosis drug discovery. Curr Opin Biotechnol 48, 94-101.
Suarez, I., Lehmann, C., Gruell, H., Graeb, J., Kochanek, M., Fatkenheuer, G., Plum, G., van Wengen, A., van de Vosse, E., Hartmann, P., Hanitsch, L.G., and Rybniker, J. (2017). Repurposing QuantiFERON for Detection of Neutralizing Interferon-gamma Autoantibodies in Patients With Nontuberculous Mycobacterial Infections. Clin Infect Dis 65, 518-21.
Suarez, I., Roderus, L., van Gumpel, E., Jung, N., Lehmann, C., Fatkenheuer, G., Hartmann, P., Plum, G., and Rybniker, J. (2017). Low prevalence of DHFR and DHPS mutations in Pneumocystis jirovecii strains obtained from a German cohort. Infection 45, 341-7.
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Comprehensive host-cell based antibiotic drug discovery
Clinic I of Internal Medicine & Center for Molecular Medicine Cologne - CMMC Research Building
CMMC - PI - B 10
CMMC - former PI - CAP 08
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Clinic I of Internal Medicine & Center for Molecular Medicine Cologne - CMMC Research Building
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Prof. Dr. med. Thomas Benzing
Chair of the CMMC
