دورية أكاديمية
أعرض في EDS

Repurposing Tamoxifen as Potential Host-Directed Therapeutic for Tuberculosis.

التفاصيل البيبلوغرافية
العنوان: Repurposing Tamoxifen as Potential Host-Directed Therapeutic for Tuberculosis.
المؤلفون: Boland R; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands., Heemskerk MT; Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands., Forn-Cuní G; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands., Korbee CJ; Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands., Walburg KV; Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands., Esselink JJ; Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands., Carvalho Dos Santos C; Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.; Laboratório Especial de Desenvolvimento de Vacinas, Instituto Butantan, São Paulo, Brazil., de Waal AM; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands., van der Hoeven DCM; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands., van der Sar E; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands., de Ries AS; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands., Xie J; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands., Spaink HP; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands., van der Vaart M; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands., Haks MC; Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands., Meijer AH; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands., Ottenhoff THM; Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
المصدر: MBio [mBio] 2023 Feb 28; Vol. 14 (1), pp. e0302422. Date of Electronic Publication: 2022 Dec 07.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 101519231 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2150-7511 (Electronic) NLM ISO Abbreviation: mBio Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Society for Microbiology
مواضيع طبية MeSH: Tuberculosis*/microbiology , Mycobacterium tuberculosis*/genetics, Animals ; Humans ; Zebrafish ; Tamoxifen/pharmacology ; Tamoxifen/therapeutic use ; Drug Repositioning ; Antitubercular Agents/pharmacology ; Antitubercular Agents/therapeutic use
مستخلص: The global burden of tuberculosis (TB) is aggravated by the continuously increasing emergence of drug resistance, highlighting the need for innovative therapeutic options. The concept of host-directed therapy (HDT) as adjunctive to classical antibacterial therapy with antibiotics represents a novel and promising approach for treating TB. Here, we have focused on repurposing the clinically used anticancer drug tamoxifen, which was identified as a molecule with strong host-directed activity against intracellular Mycobacterium tuberculosis ( Mtb ). Using a primary human macrophage Mtb infection model, we demonstrate the potential of tamoxifen against drug-sensitive as well as drug-resistant Mtb bacteria. The therapeutic effect of tamoxifen was confirmed in an in vivo TB model based on Mycobacterium marinum infection of zebrafish larvae. Tamoxifen had no direct antimicrobial effects at the concentrations used, confirming that tamoxifen acted as an HDT drug. Furthermore, we demonstrate that the antimycobacterial effect of tamoxifen is independent of its well-known target the estrogen receptor (ER) pathway, but instead acts by modulating autophagy, in particular the lysosomal pathway. Through RNA sequencing and microscopic colocalization studies, we show that tamoxifen stimulates lysosomal activation and increases the localization of mycobacteria in lysosomes both in vitro and in vivo , while inhibition of lysosomal activity during tamoxifen treatment partly restores mycobacterial survival. Thus, our work highlights the HDT potential of tamoxifen and proposes it as a repurposed molecule for the treatment of TB. IMPORTANCE Tuberculosis (TB) is the world's most lethal infectious disease caused by a bacterial pathogen, Mycobacterium tuberculosis. This pathogen evades the immune defenses of its host and grows intracellularly in immune cells, particularly inside macrophages. There is an urgent need for novel therapeutic strategies because treatment of TB patients is increasingly complicated by rising antibiotic resistance. In this study, we explored a breast cancer drug, tamoxifen, as a potential anti-TB drug. We show that tamoxifen acts as a so-called host-directed therapeutic, which means that it does not act directly on the bacteria but helps the host macrophages combat the infection more effectively. We confirmed the antimycobacterial effect of tamoxifen in a zebrafish model for TB and showed that it functions by promoting the delivery of mycobacteria to digestive organelles, the lysosomes. These results support the high potential of tamoxifen to be repurposed to fight antibiotic-resistant TB infections by host-directed therapy.
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فهرسة مساهمة: Keywords: AMR; HDT; MDR; host-directed therapeutic; human macrophages; lysosomal acidification; tamoxifen; tuberculosis; zebrafish model
المشرفين على المادة: 094ZI81Y45 (Tamoxifen)
0 (Antitubercular Agents)
تواريخ الأحداث: Date Created: 20221208 Date Completed: 20230302 Latest Revision: 20230314
رمز التحديث: 20230314
مُعرف محوري في PubMed: PMC9973281
DOI: 10.1128/mbio.03024-22
PMID: 36475748
قاعدة البيانات: MEDLINE
الوصف
تدمد:2150-7511
DOI:10.1128/mbio.03024-22