Use of tamoxifen derivatives in combination with colistin against colistin-resistant Acinetobacter baumannii

Abstract

Abstract We aimed to discover new tamoxifen derivatives with antimicrobial potential, particularly targeting colistin-resistant Acinetobacter baumannii. We determined the MIC of 22 tamoxifen derivatives against both A. baumannii wild-type and colistin-resistant strains using microdilution assays, in monotherapy and in combination with colistin. The antibacterial effects of selected tamoxifen derivatives, in monotherapy and in combination with colistin, against colistin-resistant A. baumannii (Ab22), were assessed through bacterial growth assays. Changes in bacterial membrane permeability and the profile of outer membrane proteins (OMPs) were analyzed by using fluorescence assays and SDS-PAGE, respectively. The MIC of the tamoxifen derivatives in monotherapy exceed 64 mg/L. However, the combination of tamoxifen derivatives (1), (14), and (18) with colistin displayed MIC between 0.125 and 2 μg/mL for the reference ATCC 17978 strain and between 0.5 and 1 μg/mL for the colistin-resistant Ab22 strain. Bacterial growth assays demonstrated that tamoxifen derivatives (1), (14), and (18) delayed the growth of the Ab22 strain during the first 4 h. Moreover, treatment with these derivatives resulted in increased membrane permeabilization without affecting the expression of OMPs. These data suggest that tamoxifen derivatives exhibit antibacterial activity against colistin-resistant A. baumannii, potentially broadening the spectrum of available drug treatments for combating antimicrobial-resistant Gram-negative bacilli.