Projektbeschreibung
Eine genetische Methode zur Bestimmung der Achillesferse von Bakterien
Die Antibiotikaresistenz ist zu einer weltweiten Gesundheitsbedrohung geworden, die chirurgischen Behandlungserfolgen entgegensteht und eigentlich behandelbare Erkrankungen zum Problem macht. Es ist daher dringend erforderlich, die entscheidenden Einflussfaktoren der Antibiotikaresistenz eingehender zu verstehen und Möglichkeiten zu finden, um ihnen entgegenzuwirken. Das EU-finanzierte Projekt uCARE wird von der Hypothese ausgehen, dass Bakterien gegen Antibiotika und Wirkstoffe, die auf menschliche Moleküle abzielen, ähnliche Resistenzmechanismen nutzen. Zur Erforschung dieser gemeinsamen Resistenzmechanismen und Netzwerke wird das Projektteam auf chemische Genetik und experimentelle Evolution setzen. Das Projekt wird Erkenntnisse über die Entwicklung von Resistenzen gegenüber Wirkstoffen für den Menschen liefern und damit eine Grundlage zur Überarbeitung von bisherigen Arzneimittelrichtlinien bieten.
Ziel
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.
Wissenschaftliches Gebiet
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- natural sciencesbiological sciencesgenetics
- medical and health scienceshealth sciencespublic health
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibiotics
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
69117 Heidelberg
Deutschland