Abstract
The development of new strategic antimicrobial therapeutic approaches, such as drug repurposing, has become an urgent need. Previously, we reported that tamoxifen presents therapeutic efficacy against multidrug-resistant (MDR) Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli in experimental infection models by modulating innate immune system cell traffic. The main objective of this study was to analyze the activity of N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen, three major metabolites of tamoxifen, against these pathogens. We showed that immunosuppressed mice infected with A. baumannii, P. aeruginosa, or E. coli in peritoneal sepsis models and treated with tamoxifen at 80 mg/kg/d for three days still reduced the bacterial load in tissues and blood. Moreover, it increased mice survival to 66.7% (for A. baumannii and E. coli) and 16.7% (for P. aeruginosa) when compared with immunocompetent mice. Further, susceptibility and time-kill assays showed that N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen exhibited minimum inhibitory concentration of the 90% of the isolates (MIC90) values of 16 mg/L, and were bactericidal against clinical isolates of A. baumannii and E. coli. This antimicrobial activity of tamoxifen metabolites paralleled an increased membrane permeability of A. baumannii and E. coli without affecting their outer membrane proteins profiles. Together, these data showed that tamoxifen metabolites presented antibacterial activity against MDR A. baumannii and E. coli, and may be a potential alternative for the treatment of infections caused by these two pathogens.
Highlights
Anticancer drugs developed to combat breast cancer, such as selective estrogen receptor modulators (SERMs), have been reported to present activity against Gram-positive bacteria [1]
A previous study from our research group showed that tamoxifen played an essential role in regulating immune cell traffic after infection by Gram-negative bacilli (i.e., Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli) in order to reduce the hyperinflammation caused by sepsis and the bacterial burdens in animal tissues and fluids [1]
To determine whether tamoxifen treatment is therapeutically effective in immunosuppressed mice, we treated immunocompetent mice with cyclophosphamide to reduce circulating monocytes and neutrophils
Summary
Anticancer drugs developed to combat breast cancer, such as selective estrogen receptor modulators (SERMs), have been reported to present activity against Gram-positive bacteria [1]. Clomiphene has demonstrated efficacy against Enterococcus faecium and Staphylococcus aureus through inhibiting undecaprenyl diphosphate synthase (UPPS), an enzyme involved in the synthesis of the teichoic acid wall of S. aureus [2,3] Due to this action on the bacterial wall, clomiphene exhibits synergy with β-lactams in restoring methicillinresistant S. aureus susceptibility [3]. As with other antimicrobial agents like colistimethate sodium [5], tamoxifen is a prodrug converted after liver passage to three major active metabolites: 4-hydroxytamoxifen (HTAM), endoxifen (ENDX), and N-desmethyltamoxifen (DTAM) [6]. Their antibacterial activities against Gram-negative bacteria remain unknown
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