Repurposing of the Tamoxifen Metabolites to Combat Infections by Multidrug-Resistant Gram-Negative Bacilli
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) <i>Acinetobacter baumannii</i>, <i>Pseudomonas aerugino...
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| Main Authors: | , , , , , |
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| Format: | Book |
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MDPI AG,
2021-03-01T00:00:00Z.
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| Summary: | 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) <i>Acinetobacter baumannii</i>, <i>Pseudomonas aeruginosa</i>, and <i>Escherichia coli</i> 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 <i>A. baumannii</i>, <i>P. aeruginosa</i>, or <i>E. coli</i> 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 <i>A. baumannii</i> and <i>E. coli</i>) and 16.7% (for <i>P. aeruginosa</i>) 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 (MIC<sub>90</sub>) values of 16 mg/L, and were bactericidal against clinical isolates of <i>A. baumannii</i> and <i>E. coli</i>. This antimicrobial activity of tamoxifen metabolites paralleled an increased membrane permeability of <i>A. baumannii</i> and <i>E. coli</i> without affecting their outer membrane proteins profiles. Together, these data showed that tamoxifen metabolites presented antibacterial activity against MDR <i>A. baumannii</i> and <i>E. coli</i>, and may be a potential alternative for the treatment of infections caused by these two pathogens. |
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| Item Description: | 10.3390/antibiotics10030336 2079-6382 |