Eva Mezeiova

PC23 – Eva Mezeiova

Biomedical Research Centre, University Hospital Hradec Králové

ORCID

eva.mezeiova@fnhk.cz

Substituted Cinnamylpiperazines as Modulators of AcrAB-TolC-Mediated Antibiotic Resistance
Mezeiova Eva¹, Kufa Martin ^1,2, Hympanova Michaela¹, Korabecny Jan¹ and Roh Jaroslav² ¹ Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 50005, Hradec Kralove, The Czech Republic ² Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 50005, Hradec Kralove, The Czech Republic
Abstract The rapid spread of antibiotic resistance represents a major threat to effective antimicrobial therapy worldwide. In Gram-negative bacteria, resistance is frequently mediated by multidrug efflux systems that actively expel antibiotics from the cell, thereby reducing intracellular drug exposure and treatment efficacy. Among these systems, the AcrAB-TolC efflux pump of Escherichia coli is one of the most prominent and extensively investigated resistance determinants. In the present work, we describe the design, synthesis, and biological evaluation of a series of substituted cinnamylpiperazine derivatives as potential efflux pump inhibitors targeting the AcrAB-TolC system.[1] The ability of the compounds to restore antibiotic activity was assessed using both wild-type E. coli strains and strains deficient in efflux pump function, allowing mechanistic insight into their mode of action. The observed activity profiles strongly support AcrAB-TolC as the primary target of the investigated molecules.[2] One representative compound, K2855, demonstrated pronounced synergistic effects in combination with selected antibiotics, yielding fractional inhibitory concentration indices of 0.33 with linezolid and 0.31 with erythromycin in checkerboard assays. These results are comparable to those obtained with the reference inhibitor phenylalanine-arginine β-naphthylamide and exceed the performance of the structurally related inhibitor 1-(1-naphthylmethyl)piperazine. Taken together, our findings identify substituted cinnamylpiperazines as a promising chemical class for efflux pump inhibition and highlight their potential to counteract bacterial resistance by enhancing the efficacy of existing antibiotics. Further studies are underway to refine structure–activity relationships and to improve the pharmacokinetic and pharmacodynamic properties of this scaffold.
References [1] Okeke, N.I.; de Kraker M.E.A.; Boeckel, T.P.V; Kumar, C.K.; Schmitt, H.; Gales, A.C.; Bertagnolio, S.; Sharland, M.; Laxminarayan, R. The scope of the antimicrobial resistance challenge. The Lancet 2024, 403, 2426–2438. https://doi.org/10.1016/S0140-6736(24)00876-6. [2] Langevin, A.M.; El Meouche, I.; Dunlop, M.J. Mapping the Role of AcrAB-TolC Efflux Pumps in the Evolution of Antibiotic Resistance Reveals Near-MIC Treatments Facilitate Resistance Acquisition. MSphere 2020, 5. https://doi.org/10.1128/msphere.01056-20. Acknowledgment: The study was supported by project no. NW24-08-00135 from the Czech Health Research Council.