Publication:
Repurposing of the Tamoxifen Metabolites to Combat Infections by Multidrug-Resistant Gram-Negative Bacilli

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Date

2021-03-22

Authors

Miró-Canturri, Andrea
Ayerbe-Algaba, Rafael
Vila-Domínguez, Andrea
Jiménez-Mejías, Manuel E.
Pachón, Jerónimo
Smani, Younes

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MDPI
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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.

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MeSH Terms

Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice
Medical Subject Headings::Organisms::Eukaryota::Animals
Medical Subject Headings::Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Aerobic Bacteria::Gram-Negative Aerobic Rods and Cocci::Moraxellaceae::Acinetobacter::Acinetobacter baumannii
Medical Subject Headings::Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Aerobic Bacteria::Gram-Negative Aerobic Rods and Cocci::Pseudomonadaceae::Pseudomonas::Pseudomonas aeruginosa
Medical Subject Headings::Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Facultatively Anaerobic Rods::Enterobacteriaceae::Escherichia::Escherichia coli
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Clinical Laboratory Techniques::Microbiological Techniques::Bacteriological Techniques::Bacterial Load
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Drug Discovery::Drug Repositioning
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Hydrocarbons, Cyclic::Hydrocarbons, Aromatic::Benzene Derivatives::Benzylidene Compounds::Stilbenes::Tamoxifen
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Clinical Laboratory Techniques::Microbiological Techniques::Microbial Sensitivity Tests
Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Anti-Bacterial Agents
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins
Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents
Medical Subject Headings::Anatomy::Hemic and Immune Systems::Immune System
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Permeability
Medical Subject Headings::Diseases::Bacterial Infections and Mycoses::Infection::Sepsis

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Keywords

Tamoxifen, Tamoxifen metabolite, Bacteria, Infection, Treatment, Tamoxifeno, Infección, Terapéutica, Bacterias

Citation

Miró-Canturri A, Ayerbe-Algaba R, Vila-Domínguez A, Jiménez-Mejías ME, Pachón J, Smani Y. Repurposing of the Tamoxifen Metabolites to Combat Infections by Multidrug-Resistant Gram-Negative Bacilli. Antibiotics. 2021 Mar 22;10(3):336