Rybniker, Jan - CAP 8

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