A new substrate triggers susceptibility by uncoupling a bacterial multidrug resistance efflux pump
Spreacker, P. J.; Thomas, N. E.; Beeninga, W. F.; Brousseau, M.; Hibbs, K. M.; Henzler-Wildman, K. A.
10.1101/2021.12.04.471113 bioRxivShow abstract
Small multidrug resistance (SMR) transporters contribute to antibiotic resistance through proton-coupled efflux of toxic compounds from the bacterial cytoplasm. Previous biophysical studies of the E. coli SMR transporter EmrE suggested that it should also be capable of performing proton/toxin symport or uniport, leading to toxin susceptibility rather than resistance in vivo. Here we show EmrE does confer susceptibility to several newly characterized small-molecule substrates in E. coli, including harmane. In vitro experiments show that harmane binding to EmrE triggers uncoupled proton uniport and this protein-mediated dissipation of the transmembrane pH gradient underlies the in vivo phenotype. This leads to synergy with some existing antibiotics, such as kanamycin. Furthermore, this shows that it is possible to not just inhibit multidrug efflux but activate alternative transport modes that are detrimental to bacterial growth and metabolism.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Molecular basis of the urate transporter URAT1 inhibition by gout drugs 98%
- Structure of a lasso peptide bound ETB receptor provides insights into the mechanism of GPCR inverse agonism 97%
- Structure and mechanism of oxalate transporter OxlT in an oxalate-degrading bacterium in the gut microbiota 97%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.