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Understanding Circumventing Antibiotic REsistance

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.

Field of science

  • /medical and health sciences/health sciences/public and environmental health
  • /medical and health sciences/basic medicine/pharmacology and pharmacy/pharmaceutical drug
  • /natural sciences/biological sciences/genetics and heredity
  • /medical and health sciences/basic medicine/pharmacology and pharmacy/drug resistance/antibiotic resistance
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/proteomics

Call for proposal

ERC-2018-COG
See other projects for this call

Funding Scheme

ERC-COG - Consolidator Grant

Host institution

EUROPEAN MOLECULAR BIOLOGY LABORATORY
Address
Meyerhofstrasse 1
69117 Heidelberg
Germany
Activity type
Research Organisations
EU contribution
€ 1 986 004

Beneficiaries (1)

EUROPEAN MOLECULAR BIOLOGY LABORATORY
Germany
EU contribution
€ 1 986 004
Address
Meyerhofstrasse 1
69117 Heidelberg
Activity type
Research Organisations