Genetic modules for sensing and detoxification of novel antibacterial compounds

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The Gram positive bacterium Listeria monocytogenes is the causative agent of listeriosis. Listeriosis is an infectious human disease with high mortality and acquired through the consumption of contaminated food. L. monocytogenes is ubiquitously present in the soil, in surface water and on plant surfaces or in the gut of animals. Because of this widespread occurrence, the bacterium frequently enters the food chain and regularly causes large disease outbreaks with many deaths. Different set of genes and their precise expression facilitate the survival of L. monocytogenes in its natural habitats outside the human body or during human infection.Many of the virulence factors of L. monocytogenes are known and in many cases their regulation is well-understood. In contrast, less information is available on the genes that contribute to the survival of L. monocytogenes in the environment. However, an improved knowledge on the molecular mechanisms ensuring the survival of this pathogen in its natural habitats could help to reduce the risk of food contaminations by L. monocytogenes in the future.Sequence analyses have revealed the presence of 23 so far uncharacterized multi drug resistance (MDR) ABC transporters in the genome of L. monocytogenes. These transporters are supposed to facilitate the export of toxic compounds out of the bacterial cell. Our own research on the MDR transporter LieAB demonstrated that natural antimicrobial compounds such as aurantimycin A are among the substrates of these MDR transporters. Aurantimycin A is an antibiotic produced by another soil-dwelling bacterium and probably synthesized to inhibit the growth of competing species. The 23 so far unstudied MDR transporters and their function should be investigated in this project proposal. For this purpose, a natural compound library should be screened to identify MDR transporters conferring resistance against selected compounds in this library and/or to identify MDR transporters the expression of which is induced by some of these compounds. The underlying molecular mechanisms of compound sensing and compound detoxification should then be studied in more detail.In the second part of the proposed project, the mechanisms of sensing and detoxification of aurantimycin A by LieAB and by further associated proteins should be studied using genetic and biochemical approaches as well as protein crystallography. The expected results should improve our understanding of the ecological interactions of L. monocytogenes in its natural environment and should help to better specify the reservoir of this important human pathogen.