2026-10-14T11:20:58Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33979468 2026-09-24T04:33:34Z category_19 portal_316 item_type_3 month_year_09_2026

Data Sheet 1_Targeting the AcrAB-TolC efflux pump by small molecules selectively addressing the outer membrane factor TolC.pdf Janis Veliks (1719760) Cristina D. Cruz (6198668) Tania Szal (25101973) Marina Madre (4786485) Irena Leite (24542235) Laura Paunina (25101976) Philipp Lewe (12910454) Maren Hinz (25101979) Susanne Witt (3149961) Päivi Tammela (191448) Aigars Jirgensons (1435216) Björn Windshügel (559585) Pharmacology AcrAB-TolC antimicrobial resistance E. coli efflux pumps outer membrane factor TolC Background<p>Gram-negative bacteria express several efflux pump complexes extruding a broad spectrum of antibiotics. The major efflux pump in E. coli is the AcrAB-TolC complex that expels a broad spectrum of antibiotics from the bacterium, resulting in impaired efficacy of these drugs. Therefore, the inhibition of efflux pump function is an attractive approach to restore the susceptibility of Gram-negative bacteria for antibiotics.</p>Methods<p>A virtual screening campaign was utilized to identify potential TolC binders. Virtual hits were investigated using a functional efflux assay, followed by synergy tests with piperacillin and determination of the intrinsic antibacterial potential. Bindings studies with individual efflux pump proteins were carried out. Synthetic chemistry was applied to improve the efficacy of the compound. Microbiological and biophysical tests were used to characterize the compounds with respect to synergistic activity with antibiotics and efflux pump binding.</p>Results<p>We identified a small molecule interfering with efflux pump function, showing synergistic activity with piperacillin and binding to TolC which was further optimized at various positions. The most promising compounds revealed TolC-selective binding and shifted the minimum inhibitory concentration of piperacillin and levofloxacin at low micromolar concentrations.</p>Conclusion<p>Our study provides evidence that TolC may represent a valid target for the development of an antibiotic adjuvant.</p> 2026-09-24T04:33:34Z Dataset Dataset 10.3389/fphar.2026.1895729.s001 https://figshare.com/articles/dataset/Data_Sheet_1_Targeting_the_AcrAB-TolC_efflux_pump_by_small_molecules_selectively_addressing_the_outer_membrane_factor_TolC_pdf/33979468 CC BY 4.0