GSE210309
Pyrrole-based inhibitors of RND-type efflux pumps reverse antibiotic resistance and display antivirulence potential
Efflux pumps of the resistance-nodulation-division (RND) superfamily, particularly the AcrAB-TolC and MexAB-OprM, besides mediating intrinsic and acquired resistance, also intervene in bacterial pathogenicity. Inhibitors of such pumps could restore activities of antibiotics and curb bacterial virulence. Here, we identify pyrrole-based compounds that boost antibiotic activity in Escherichia coli and Pseudomonas aeruginosa by inhibiting their archetype RND transporters. The discovered efflux pump inhibitors (EPIs) inhibit the efflux of fluorescent probes, attenuate persister formation, and diminish resistant mutant development. Molecular docking and biophysical studies revealed that the EPIs bind to AcrB. EPIs also possess an anti-pathogenic potential and attenuate P. aeruginosa virulence in vivo. The excellent efficacy of the EPI-antibiotic combination was evidenced in animal lung infection and sepsis protection models. These findings indicate that EPIs discovered herein with no off-target effects and negligible toxicity are potential antibiotic adjuvants to address life-threatening bacterial infections. Overall design: Comparative analysis of the the transcriptional profile of P. aeruginosa PAO1 in the presence and absence of sub-inhibitory concentration of Ar5 and PAßN