Project: Restoring E. coli Sensitivity for Antibiotics by blocking TolC-Mediated Efflux

Acronym	RESET-ME (Reference Number: JPIAMR_2018_P007)
Duration	01/01/2019 - 31/12/2021
Project Topic	Overexpression of efflux pumps is a major factor for drug resistance in Gram-negative bacteria. In E. coli, the AcrAB-TolC efflux pump complex transports antibiotics from the periplasm or cytoplasm into the external medium. As TolC deletion has been shown to result in increased susceptibilities of E. coli to several antibiotics, it may represent an attractive drug target. Recently, we have identified the first organic small molecule that effectively blocks TolC function using virtual screening in combination with experimental validation of the in silico hits by surface plasmon resonance (SPR) and electrophysiology studies. Building on these results, we propose to further develop this compound and in parallel to identify and develop novel TolC blockers within an interdisciplinary consortium. The already known blocker will be progressed in three rounds of optimisation. Each round comprises compound modifications by medicinal chemistry, assessment of TolC binding and blockage using SPR and electrophysiology, various antimicrobial studies and ADMETox profiling. Novel small molecules blocking TolC will be identified and optimised using the same experimental platform, starting with virtual screening for identification of novel compounds targeting TolC. Experimentally validated TolC blockers will be progressed in two rounds of optimisation. Ultimately, this approach will allow to assess TolC target validity for adjuvants in antimicrobial therapies and result in potent TolC blockers that may be further developed into drugs restoring E. coli susceptibility to antibiotics.
Website	visit project website
Network	JPI AMR
Call	6th Joint Call of JPIAMR

Project partner

Number	Name	Role	Country
1	Fraunhofer Institute for Molecular Biology and Applied Ecology	Coordinator	Germany
2	Jacobs University Bremen	Partner	Germany
3	University of Helsinki	Partner	Finland
4	Latvian Institute of Organic Synthesis	Partner	Latvia
5	University of Cagliari	Observer	Italy