Project-ID: LS16-005
Project start: 01. Jänner 2018
Project end: will follow
Runtime: 36 months / ongoing
Funding amount: € 279.000,00

Brief summary:

For decades virtually every easily cultivable microorganism has been investigated in pharmaceutical highthrough put screens (HTP) for natural bioactive compound production and after observation of a constantly increasing rediscovery rate of bioactive compounds the source was declared empty. As a consequence; large scale screening programs for natural bioactive compounds were mostly terminated. However, in recent years, the interest in natural bioactive compounds has been reignited based on mass sequencing results of microbial genomes predicting a much richer diversity of microbial metabolites than previously anticipated. These so called “cryptic” metabolites hold the potential for novel antibiotics, direly needed for the armsrace against the ever increasing incidence of pathogenic resistance. A promising approach to activate the production of “cryptic” metabolites is co-cultivation of competing microorganisms. For example fungi and bacteria are talented producers of natural compounds with potentially strong bioactive functions. In a previous work we could demonstrate that small chemical effectors induce or increase the production of otherwise repressed compounds in fungi which raises the chance of discovery of novel compounds. In addition it has been demonstrated that biotrophic conditions influence the production of bioactive compounds in fungi. Thus as innovative screening attempt we propose a high throughput assay combining small chemical effector treatment with combinatorial growth of fungi and bacteria under various biotrophic conditions. We will realize an automated HTP pipeline to co-cultivate 144 selected bacterial strains with 32 different fungi using 4 small chemical effectors under 4 biotrophic conditions. The 73728 so produced culture extracts will be screened for their ability to counteract microbial resistance in a direct approach for the presence of novel antibiotic compounds not susceptible to commonly found microbial resistances from human sources in Lower Austria. Furthermore, in an indirect screening approach we will generate reporter strains primed for the presence of erm or cfr methylase mediated antibiotic resistance inhibitors. These resistance mechanisms are based on methylation of 16S rRNA which mediates resistance against several antibiotics at the same time and so far no in vivo active inhibitor has been discovered.
The proposed project will deliver a co-cultivation HTP pipeline and a highly divers set of HTP assays for target driven screening attempts and has the potential to discover novel bioactive compounds.

Keywords:
Antibiotic research, genetics, bacteriology and mycology