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

descriptionPublicationkeyboard_double_arrow_right Article , Other literature type 22 Mar 2021 Spain English Publisher:MDPI AGJournal:Antibiotics, volume 10, page 336 (eissn: 2079-6382,

Copyright policy )

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

doi: 10.3390/antibiotics10030336

pmid: 33810067

pmc: PMC8004611

handle: 11441/108395 , 10261/261475 , 10668/3754

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

- Summary
- Subjects
- Metrics

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.

Country

Spain

Related Organizations

University of Seville
Spain
Hospital Universitario Sanitas Virgen del Mar
Spain
Spanish National Research Council
Spain
Universidad de Sevilla (US)
Spain
Hospital Universitario Virgen del Rocío
Spain

View all View all

Keywords

Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins, Terapéutica, 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, tamoxifen metabolite, RM1-950, Article, 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, Infección, Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Clinical Laboratory Techniques::Microbiological Techniques::Bacteriological Techniques::Bacterial Load, Tamoxifeno, bacteria, tamoxifen, treatment, Bacteria, Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Permeability, Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice, Medical Subject Headings::Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Aerobic Bacteria::Gram-Negative Aerobic Rods and Cocci::Moraxellaceae::Acinetobacter::Acinetobacter baumannii, Tamoxifen metabolite, infection, Treatment, Medical Subject Headings::Organisms::Eukaryota::Animals, Tamoxifen, Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Hydrocarbons, Cyclic::Hydrocarbons, Aromatic::Benzene Derivatives::Benzylidene Compounds::Stilbenes::Tamoxifen, Medical Subject Headings::Anatomy::Hemic and Immune Systems::Immune System, Therapeutics. Pharmacology, Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Drug Discovery::Drug Repositioning, Medical Subject Headings::Diseases::Bacterial Infections and Mycoses::Infection::Sepsis, Bacterias, Infection, Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents

Impact byBIP!

	selected citations These citations are derived from selected sources. This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).	20
	popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.	Top 10%
	influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).	Average
	impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.	Top 10%