Metabolomics reveal potential natural substrates of AcrB in Escherichia coli and Salmonella enterica serovar Typhimurium

Xuan Wang-Kan, Giovanny Rodríguez-Blanco, Catherine L Winder, Andrew D. Southam, Warwick B Dunn, Alasdair Ivens, Laura J.V. Piddock

Research output: Contribution to journalArticlepeer-review


In the fight against antibiotic resistance, drugs that target resistance mechanisms in bacteria can be used to restore the therapeutic effectiveness of antibiotics. The multidrug resistance efflux complex AcrAB-TolC is the most clinically relevant efflux pump in Enterobacterales and is a target for drug discovery. Inhibition of the pump protein AcrB allows the intracellular accumulation of a wide variety of antibiotics, effectively restoring their therapeutic potency. To facilitate the development of AcrB efflux inhibitors, it is desirable to discover the native substrates of the pump, as these could be chemically modified to become inhibitors. We analyzed the native substrate profile of AcrB in Escherichia coli MG1655 and Salmonella entericaserovar Typhimurium SL1344 using an untargeted metabolomics approach. We analyzed the endo- and exometabolome of the wild-type strain and their respective AcrB loss-of-function mutants (AcrB D408A) to determine the metabolites that are native substrates of AcrB. Although there is 95% homology between the AcrB proteins of S. Typhimurium and E. coli, we observed mostly different metabolic responses in the exometabolomes of the S. Typhimurium and E. coli AcrB D408A mutants relative to those in the wild type, potentially indicating a differential metabolic adaptation to the same mutation in these two species. Additionally, we uncovered metabolite classes that could be involved in virulence of S. Typhimurium and a potential natural substrate of AcrB common to both species.
Original languageEnglish
Article numbere00109-21
Number of pages14
Issue number2
Early online date30 Mar 2021
Publication statusE-pub ahead of print - 30 Mar 2021


  • AcrAB
  • AcrAB-TolC
  • physiological substrates
  • efflux
  • enterobacterales
  • escherichia coli
  • salmonella
  • drug efflux
  • efflux pumps


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