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Research project: DINaMid
 
Genomics-guided discovery of new antimicrobials using microfluidic devices
Project time: 01.10.09-30.09.12
Cluster coordinator: Dr. Markus Nett, Hans-Knöll-Institut Jena (HKI), Jena
Project partners: (alphabetical order)
   Dr. Thomas Henkel, Institut für Photonische Technologien e.V.
   Dr. Markus Nett, Hans-Knöll-Institut Jena (HKI)
   Dr. Martin Roth, Hans-Knöll-Institut Jena (HKI)

      Overview subprojects


Increasing numbers of microbial resistance against antibiotics have spurred the need for new therapeutics. The inherent structural diversity and biological activity associated with natural products make these compounds ideal candidates for drug discovery. In recent years, genome sequencing projects have substantiated that the potential of microorganisms for the biosynthesis of secondary metabolites is far from being exhausted, prompting a resurgence in natural product research. Through the application of genome mining strategies, it has become possible to selectively screen for new metabolites, while eliminating the redundant isolation of previously described compounds.
Within the GenoMik Transfer programme, we pursue a new concept in genomics-based drug discovery exploiting microfluidic devices. Many biosynthetic pathways are subject to a complex regulation, which responds to foreign signals. By variation of cultivation parameters, it is possible to trigger the expression of silent gene clusters and as a consequence to induce metabolic changes. The implementation of such a process on a customized chip-based platform allows high throughput rates, which makes it highly attractive for industrial applications. To this end, discrete microcultures of select antibiotic producing bacteria are generated via a two-phase segmented flow. After a short incubation phase allowing a nutrient-dependent and segment-specific production of secondary metabolites, the cultures are merged with droplets containing GFP expressing reporter organisms. The growth of the latter is monitored by automated detection using a fluorescence microscope. New natural products are structurally characterized following a scale-up by means of spectroscopic analyses that are backed by bioinformatic predictions.

References:

1. Martin, K., Henkel, T., Baier, V., Grodrian, A., Schön, T, Roth, M., Köhler, J. M., Metze, J. (2003) Generation of larger numbers of separated microbial populations by cultivation in segmented-flow microdevices. Lab Chip 3, 202-207.
2. Nett, M., Ikeda, H., Moore, B. S. (2009) Genomic basis for natural product biosynthetic diversity in the actinomycetes. Nat. Prod. Rep. 26, 1362-1384.