Fig 1. Secondary metabolite-mediated regulation of multidrug resistance efflux pumps.

a. Secondary metabolites induce the expression of efflux systems, which export the metabolite. The increased expression of efflux pumps can provide collateral resilience to antibiotics used in the clinic by expelling the drugs out of the microbial cells. b. Structures of known efflux pump-regulating secondary metabolites and selected clinical antibiotics, showing the shared prevalence of aromatic and/or heterocyclic ring motifs. c. SoxR-regulated efflux systems in Escherichia coli and Pseudomonas aeruginosa. Each SoxR monomer contains a Fe–S cluster that can be directly oxidized by redox-active molecules, which leads to its activation and transcriptional induction of efflux systems^162,163. In E. coli (top), several molecules can induce transcription of the efflux system AcrAB–TolC through the activation of SoxR^162,164,165. Note that acrAB and tolC are transcribed separately, and this is a simplified version of a very complex regulatory system²². Importantly, TolC can assemble with efflux systems from different classes, such as AcrAB–TolC and several others from the resistance-nodulation-division (RND) efflux systems superfamily, EmrAB–TolC (major facilitator superfamily), and MacAB–TolC (ABC superfamily)^23,166,167. When studying how additional secondary metabolites might affect E. coli susceptibility to antibiotics, it will be important to determine which specific efflux system TolC is part of, the regulation involved in the induction of the system, and its substrate-specificity. In P. aeruginosa (bottom), the activation of SoxR is mediated by two endogenous phenazines, 5-Me-PCA (not shown) and PYO, and leads to the induction of the efflux system MexGHI–OpmD^9,34,36,163. PYO, pyocyanin; PHZ_ox, phenazine in the oxidized state; PHZ_red, phenazine in the reduced state; RAM_ox, redox-active molecule in oxidized state, RAM_red, redox-active molecule in reduced state.