Multiresistant Gram negative bacteria pose a serious health issue. They have become resistant towards all commercially available antibiotics, so that there are no treatment options left. Thus, new ways for their treatment have to be invented. One important organelle that decisively determines the antibiotic resistance and also virulence of Gram negative bacteria is their outer membrane (OM). Its composition has great influence on the integrity of the OM barrier and thus on susceptibility to antibiotics and also impacts susceptibility to host defense mechanisms (e.g. complement system). Therefore, we aim to disturb the OM barrier function by attacking different target proteins involved in its biogenesis.
By severely disturbing the OM, Gram negative bacteria can be sensitized to antibiotics that usually cannot be used for their treatment. Additionally, antibiotic resistance may be overcome by facilitating more efficient penetration of the OM. Within our research project we identified suitable targets involved in OM biogenesis, develop screening assays allowing for medium- to high-throughput screening of small compound libraries and validate identified actives in secondary assays.
Within projects funded by the DFG and the German Center for Infection Research (DZIF) we already have identified a promising target present in several Enterobacteriaceae and developed a HTS to search for inhibitors. A HTS comprising ~480.000 small molecules has been carried out in collaboration with the European Lead Factory (ELF). Identified hits are being followed up within our DZIF-funded project. To further promote the development of hits from this screen, we recently applied for funding within the 6th call of the Joint Programming Initiative on Antimicrobial Resistance (JPI-AMR).
