Ruprecht-Karls-Universität Heidelberg
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Mack0218 - Scientist (f/m) / PhD position
Project no:
Mack0218

Project leader:

Project supervisor:
Mack, Matthias
Application deadline:
31. Jan 2019
Start of PhD project:
1. Apr 2019

Project description:

Title:
Exploration of the thiamine pyrophosphate (TPP) riboswitch as a new target for antibiotics
Summary:
We have assembled a transnational team with experts in riboswitch biology, microbiology, compound screening, structure-based drug design, organic synthesis and medicinal chemistry in order to meet the high ambitions of this project. The riboswitch biology/microbiology part of project shall be carried out in Mannheim in the group of Matthias Mack.
Riboswitches are noncoding RNAs that function as regulatory genetic elements and are mostly found in bacteria. Although some eucaryotic systems (plants, fungi, and microalgae) were reported to contain riboswitches they have not been found in animals or humans. Consequently, bacterial riboswitches represent highly specific drug targets.
The main objective of this work is to explore the thiamine pyrophosphate (vitamin B1) (TPP) riboswitch as a target for antibiotics with a focus on the ESKAPE pathogens (E. coli, K. pneumoniae, A. baumannii, P. aeruginosa, S. aureus) which all carry at least one gene for a TPP riboswitch and are on the WHO priority list.
The studies in Mannheim will be conducted to ensure that the compounds act on target and in addition the mode of action of potent compounds shall be investigated at the molecular level.
References:
(1) A. Serganov and E. Nudler Cell 2013, 152 (1–2), 17.

(2) D. B. Pedrolli, A. Matern, J. Wang, M. Ester, K. Siedler, R. Breaker, and M. Mack Nucleic Acids Res. 2012, 40 (17), 8662.

(3) Pedrolli, D. B., Kuhm, C., Sevin, D. C., Vockenhuber, M. P., Sauer, U., Suess, B. and Mack, M. 2015. Proc Natl Acad Sci U S A 112, 14054-14059.
Methods that will be used:
Establishment of an in vivo assay to measure TPP riboswitch activity
Gene deletion experiments in bacteria using a CRISPR-Cas9 system
Genome analysis of resistors
Comparative transcriptome analyses of resistors
Metabolite extractions and determination of the metabolome
Cooperation partners:
Establishment of an in vivo assay to measure TPP riboswitch activity
Gene deletion experiments in bacteria using a CRISPR-Cas9 system
Genome analysis of resistors
Comparative transcriptome analyses of resistors
Metabolite extractions and determination of the metabolome
Personal qualifications:
Strong background in microbiology, molecular biology and biochemistry; Strong interest in antibiotics and mode of action studies at the molecular level:
Keywords:
Anti-infectives, Antibiotics, Microbiology, Riboswitch, Infectious disease