Anti-Mycobacterial Activity of Tamoxifen Against Drug-Resistant and Intra-Macrophage Mycobacterium tuberculosis

Jang, Woong Sik; Kim, Sukyung; Podder, Biswajit; Jyoti, Md. Anirban; Nam, Kwanghee; Lee, Byung-Eui; Song, Ho‐Yeon

doi:10.4014/jmb.1412.12023

Cited by 36 publications

(28 citation statements)

References 18 publications

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“…Therefore, the time and the economic costs of the evaluation of these drugs in other therapeutic applications, such as the treatment of bacterial infections, will be reduced (31). Among these immunomodulatory drugs, we found tamoxifen as a promising therapeutic candidate; which has showed antifungal and antibacterial activities against Mycobacterium tuberculosis and some Gram-positive bacteria in vitro and in vivo (17, 18, 25).…”

Section: Discussionmentioning

confidence: 99%

“…In prokaryotic cells, tamoxifen is known to present antifungal and antibacterial activities against Mycobacterium tuberculosis and some Gram-positive bacteria in vitro and in vivo (17, 18), but not against Gram-negative bacteria. As with other antimicrobial agent such as colistimethate sodium (19), tamoxifen is a prodrug and converted after liver passage to three major active metabolites, 4-hydroxytamoxifen, endoxifen and N-desmethyltamoxifen (20).…”

Section: Introductionmentioning

confidence: 99%

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Tamoxifen repurposing to combat infections by multidrug-resistant Gram-negative bacilli

Miró-Canturri

Ayerbe-Algaba

Pachón

et al. 2020

Preprint

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22The development of new strategic therapies for multidrug-resistant bacteria, like the use of non-23 antimicrobial approaches and/or drugs repurposing to be used as monotherapies or in 24 combination with clinically relevant antibiotics, has become an urgent need. A therapeutic 25 alternative for infections by multidrug-resistant Gram-negative bacilli (MDR-GNB) is immune 26 system modulation to improve the infection clearance. We showed that immunocompetent mice 27 infected by Acinetobacter baumannii, Pseudomonas aeruginosa or Escherichia coli in peritoneal 28 sepsis models and treated with tamoxifen at 80 mg/kg/d for three days reduced the release of 29 MCP-1 and its signalling pathway IL-18 and phosphorylated ERK1/2. This reduction of MCP-1 30 induced the reduction of migration of inflammatory monocytes and neutrophils from bone 31 marrow to blood. Indeed, the treatment with tamoxifen in murine peritoneal sepsis models 32 reduced the bacterial load in tissues and blood; and increased the mice survival from 0% to 60-33 100%. Tamoxifen treatment of neutropenic mice infected by these pathogens increased mice 34 survival up to 20-60%. Furthermore, susceptibility and time-kill assays showed that the 35 metabolites of tamoxifen, N-desmethyltamoxifen, hydroxytamoxifen and endoxifen, the three 36 together exhibited MIC 90 values of 16 mg/L and were bactericidal against clinical isolates of A. 37 baumannii and E. coli. This antimicrobial activity of tamoxifen metabolites parallels' an 38 increased membrane permeability of A. baumannii and E. coli without affecting their outer 39 membrane proteins profiles. Together, these data showed that tamoxifen present a therapeutic 40 efficacy against MDR A. baumannii, P. aeruginosa and E. coli in experimental models of 41 infections and can be repurposed as new treatment for GNB infections. 42 43 44 Importance 45Antimicrobial resistance in Gram-negative bacilli (GNB) is a global health treat. Drug 46 repurposing, a novel approach involving the search of new indications for FDA approved drugs 47 is gaining interest. Among them, we found the anti-cancer drug tamoxifen, which presents very 48 promising therapeutic efficacy. The current study showed that tamoxifen presents activity in 49 animal models of infection with MDR Acinetobacter baumannii, Pseudomonas aeruginosa and 50 Escherichia coli by modulating the traffic of innate immune system cells and the antibacterial 51 activity presented by its three major metabolites produced in vivo against these GNB. Our results 52 offer a new candidate to be repurposed to treat severe infections caused by these pathogens. 53 54Infections caused by Gram-negative bacilli (GNB) such as Acinetobacter baumannii, 56 Pseudomonas aeruginosa and Escherichia coli represent an increasing worldwide problem. In 57 2017, the World Health Organization has listed these pathogens as the first antibiotic-resistant 58 "priority pathogens" that pose the greatest threat to human health. There is, therefore, an urgent 59 need to find new an...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tamoxifen repurposing to combat infections by multidrug-resistant Gram-negative bacilli

Miró-Canturri

Ayerbe-Algaba

Pachón

et al. 2020

Preprint

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show abstract

“…Confocal microscopy was performed in H37Ra-GFP infected Raw 264.7 cells as previously described [17]. In brief, Raw 264.7 cells were infected with H37Ra-GFP at an MOI of 1:1 in RPMI 1640 medium supplemented with 10% heat-inactivated FBS for 3 h at 37 °C with 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Thymoquinone (TQ) inhibits the replication of intracellular Mycobacterium tuberculosis in macrophages and modulates nitric oxide production

Mahmud

Seo

Kim

et al. 2017

BMC Complement Altern Med

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BackgroundHuman tuberculosis, which is caused by the pathogen Mycobacterium tuberculosis, remains a major public health concern. Increasing drug resistance poses a threat of disease resurgence and continues to cause considerable mortality worldwide, which necessitates the development of new drugs with improved efficacy. Thymoquinone (TQ), an essential compound of Nigella sativa, was previously reported as an active anti-tuberculosis agent.MethodsIn this study, the effects of TQ on intracellular mycobacterial replication are examined in macrophages. In addition, its effect on mycobacteria-induced NO production and pro-inflammatory responses were investigated in Mycobacterium tuberculosis (MTB)-infected Type II human alveolar and human myeloid cell lines.ResultsTQ at concentrations ranging from 12.5 to 25 μg/mL and 6.25 to 12.5 μg/mL reduced intracellular M. tuberculosis H37Rv and extensively drug-resistant tuberculosis (XDR-TB) 72 h post-infection in RAW 264.7 cells. TQ treatment also produced a concentration-dependent reduction in nitric oxide production in both H37Rv and XDR-TB infected RAW 264.7 cells. Furthermore, TQ reduced the expression of inducible nitric oxide synthase (iNOS) and pro-inflammatory molecules such as tumor necrosis factor-alpha (TNF-α) and interlukin-6 (IL-6) in H37Rv-infected cells and eventually reduced pathogen-derived stress in host cells.ConclusionsTQ inhibits intracellular H37Rv and XDR-TB replication and MTB-induced production of NO and pro-inflammatory molecules. Therefore, along with its anti-inflammatory effects, TQ represents a prospective treatment option to combat Mycobacterium tuberculosis infection.

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“…Cytotoxicity test. A cytotoxicity experiment was done with a water-soluble tetrazolium salt assay by using an EZ-Cytox Cell Viability Assay kit (Daeil Lab Service, Korea), as previously described (Jang et al, 2015;Castro-Garza et al, 2007). The selectivity index (SI) was then calculated by dividing the cytotoxicity values by the MIC.…”

Section: Methodsmentioning

confidence: 99%

In vitro Antitubercular Activity of 3‐Deoxysappanchalcone Isolated From the Heartwood of Caesalpinia sappan Linn.

Seo

Kim

Mahmud

et al. 2017

Phytotherapy Research

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Responsible for nearly 1.5 million deaths every year, the infectious disease tuberculosis remains one of the most serious challenges to global health. The emergence of multidrug-resistant tuberculosis and, more recently, extensively drug-resistant tuberculosis poses a significant threat in our effort to control this epidemic. New drugs are urgently needed to combat the growing threat of antimicrobial resistance. To achieve this goal, we screened approximately 500 species of medicinal plant methanol extracts and their solvent partitioned fractions for potential inhibitors of Mycobacterium tuberculosis growth. Using microdilution screening, the ethyl acetate solvent partitioned fraction from the heartwood of Caesalpinia sappan exhibited strong antitubercular activity. We isolated the active compound and identified it as 3-deoxysappanchalcone. The extracted 3-deoxysappanchalcone possessed activity against both drug-susceptible and drug-resistant strains of M. tuberculosis at MIC s of 3.125-12.5 μg/mL in culture broth and MIC s of 6.25-12.5 μg/mL inside macrophages and pneumocytes. 3-Deoxysappanchalcone was also found to act in partial synergy with streptomycin/ethambutol against M. tuberculosis H37Rv. 3-Deoxysappanchalcone had no cytotoxicity against the A549 cell line up to a concentration of 100 μg/mL (selectivity index > 8-32). Further studies are warranted to establish the in vivo effect and therapeutic potential of 3-deoxysappanchalcone. Copyright © 2017 John Wiley & Sons, Ltd.

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Anti-Mycobacterial Activity of Tamoxifen Against Drug-Resistant and Intra-Macrophage Mycobacterium tuberculosis

Cited by 36 publications

References 18 publications

Tamoxifen repurposing to combat infections by multidrug-resistant Gram-negative bacilli

Tamoxifen repurposing to combat infections by multidrug-resistant Gram-negative bacilli

Thymoquinone (TQ) inhibits the replication of intracellular Mycobacterium tuberculosis in macrophages and modulates nitric oxide production

In vitro Antitubercular Activity of 3‐Deoxysappanchalcone Isolated From the Heartwood of Caesalpinia sappan Linn.

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