Descrizione del progetto
La genetica impiegata per identificare il tallone d’Achille dei batteri
La resistenza agli antibiotici è diventata un’importante minaccia per la salute, poiché ostacola l’esito clinico degli interventi chirurgici e di altre malattie altrimenti curabili. C’è quindi un urgente bisogno di comprendere i meccanismi di resistenza agli antibiotici e di trovare metodi per contrastarli. Il progetto uCARE, finanziato dall’UE, sarà svolto sulla base dell’ipotesi che i batteri utilizzino meccanismi di resistenza simili contro antibiotici e farmaci rivolti a molecole umane. Per chiarire le reti e i meccanismi di resistenza comuni, i ricercatori utilizzeranno strumenti di genetica chimica e di evoluzione sperimentale. Svelando i meccanismi di sviluppo della resistenza a farmaci umani, il progetto contribuirà a rivedere le politiche farmacologiche attuali.
Obiettivo
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.
Campo scientifico
- 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
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
69117 Heidelberg
Germania