Project description DEENESFRITPL Employing genetics to identify the Achilles heel of bacteria Antibiotic resistance has become a major health threat, impeding the clinical outcome of surgeries and otherwise treatable diseases. Therefore, there is a pressing need to understand the drivers of antibiotic resistance and find ways to counteract them. The EU-funded uCARE project will work under the hypothesis that bacteria use similar resistance mechanisms against antibiotics and drugs that target human molecules. To elucidate the common resistance mechanisms and networks, researchers will use chemical genetics and experimental evolution. By uncovering resistance development of human-targeted drugs, the project will help revisit current medication policies. Show the project objective Hide the project objective Objective The evolution and spread of antibiotic resistance has become a public health concern of the utmost severity, making once treatable diseases deadly again and undermining our living standards. New therapies are imperative, but equally important are the understanding of the full repertoire of drivers of antibiotic resistance and the identification of ways to counteract them. We have recently established that ~250 non-antibiotic drugs have direct, strong and often broad antibacterial effects on human gut microbes. Moreover, preliminary data indicate that bacteria use similar general resistance mechanisms against both drugs with human targets and antibiotics. This implies that polypharmacy may be a hitherto unnoticed driver of antibiotic resistance. We will use chemical genetics and experimental evolution to systematically map the cross-resistance between human-targeted drugs and antibiotics, and elucidate underlying resistance mechanisms. Using these data, we will next seek to identify antidotes for the antimicrobial side-effects of non-antibiotic drugs, and exploit human-targeted drugs for reverting existing antibiotic resistance. At the genetic level, we will use high-throughput reverse genetics to expose the Achilles heels of bacterial cellular networks for resistance development. Finally, we will uncover the antimicrobial mode of action of tens of human-targeted drugs using thermal proteome profiling and chemical genetics. Together with the genetic information, this line of research will yield design principles and possibly new drug candidates for longer-lived, resistance-proof drug combinations. Overall, this project aims at improving our fundamental biological understanding of antibiotic resistance and the paths to prevent, delay or revert it. It can also set the basis for revisiting current medication policies. The derived principles are likely to be relevant to other diseases and therapies, in which resistance development is an issue. Fields of science medical and health sciencesbasic medicinepharmacology and pharmacydrug discoverynatural sciencesbiological sciencesgeneticsmedical and health scienceshealth sciencespublic healthmedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibioticsmedical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance Keywords Reverse genetics chemical genetics antibiotic resistance microbiome drug combinations genetic interactions Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2018-COG - ERC Consolidator Grant Call for proposal ERC-2018-COG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Host institution EUROPEAN MOLECULAR BIOLOGY LABORATORY Net EU contribution € 1 986 004,00 Address Meyerhofstrasse 1 69117 Heidelberg Germany See on map Region Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 986 004,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all EUROPEAN MOLECULAR BIOLOGY LABORATORY Germany Net EU contribution € 1 986 004,00 Address Meyerhofstrasse 1 69117 Heidelberg See on map Region Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 986 004,00
