BibTex format
@article{Gray:2025:10.1101/2025.08.19.671038,
author = {Gray, JL and Ledger, EVK and Suwatthee, T and Burden, TJ and Arvaniti, K and Sefton, A and Papagora, LE and Clarke, TB and Riley, J and Pinto, EG and Cunningham, F and Gilbert, IH and Gray, D and Wang, D-N and Read, KD and Lanyon-Hogg, T and Traaseth, NJ and Edwards, AM and Tate, EW},
doi = {10.1101/2025.08.19.671038},
journal = {bioRxiv},
title = {Small molecule inhibitors of the NorA multidrug efflux pump potentiate antibiotic activity by binding the outward-open conformation.},
url = {http://dx.doi.org/10.1101/2025.08.19.671038},
year = {2025}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - Antibiotic resistance is among the greatest threats of the modern era. Multidrug efflux pumps expel antibiotics from bacterial cells and present a particular challenge by conferring resistance to a broad range of antibiotic classes; however, there is currently a lack of potent and selective inhibitors. Here, we report the discovery of IMP-2380 , a drug-like chemical probe for the multidrug efflux pump NorA that delivers low-nanomolar potentiation of ciprofloxacin activity in vitro and activity in an in vivo S. aureus infection model. A phenotypic high-throughput screen for inhibitors of the ciprofloxacin-activated SOS DNA repair pathway in methicillin-resistant Staphylococcus aureus (MRSA) identified hit compounds targeting NorA, and subsequent optimization established IMP-2380 as the most potent NorA inhibitor discovered to date. The structure of NorA bound to IMP-2380 was solved by cryo-electron microscopy at 2.52 Å resolution, revealing that the small molecule locks the pump in the 'outward-open' conformation. This closes the inner face and prevents antibiotics binding from the cytosol, providing an explanation for the exceptional potency of IMP-2380 and structure-activity relationship across the series. IMP-2380 represents an in vivo active NorA inhibitor, functioning via a structurally defined outward-open binding mode, and will enable future exploration of NorA as a druggable target to combat antibiotic resistance.
AU - Gray,JL
AU - Ledger,EVK
AU - Suwatthee,T
AU - Burden,TJ
AU - Arvaniti,K
AU - Sefton,A
AU - Papagora,LE
AU - Clarke,TB
AU - Riley,J
AU - Pinto,EG
AU - Cunningham,F
AU - Gilbert,IH
AU - Gray,D
AU - Wang,D-N
AU - Read,KD
AU - Lanyon-Hogg,T
AU - Traaseth,NJ
AU - Edwards,AM
AU - Tate,EW
DO - 10.1101/2025.08.19.671038
PY - 2025///
TI - Small molecule inhibitors of the NorA multidrug efflux pump potentiate antibiotic activity by binding the outward-open conformation.
T2 - bioRxiv
UR - http://dx.doi.org/10.1101/2025.08.19.671038
UR - https://www.ncbi.nlm.nih.gov/pubmed/40894798
ER -