Repurposing Tamoxifen as Potential Host-Directed Therapeutic for Tuberculosis

Heemskerk, Matthias T.; Forn-Cuní, Gabriel; Korbee, Cornelis J.; Walburg, Kimberley V.; Esselink, Jeroen J.; Santos, C.; Waal, Amy M. de; Hoeven, Daniel C. M. van der; Sar, Elisa van der; Ries, Alex S. de; Xie, Jiajun; Spaink, Herman P.; Vaart, Michiel van der; Haks, Mariëlle C.; Meijer, Annemarie H.; Ottenhoff, Tom H. M.

doi:10.1128/mbio.03024-22

Cited by 17 publications

(7 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A model is proposed based on the data obtained from this study and previously published literature (43, 50). A comprehensive view of TCS crosstalk was reported previously (8, 30).…”

Section: Resultsmentioning

confidence: 99%

“…Tamoxifen is a clinically used anti-cancer drug that has been recently studied for its applicability in fighting antibiotic-resistant TB infections. Boland et al, have shown that tamoxifen is effective against clinical isolates of Multi-Drug Resistant (MDR) TB and inhibits bacterial growth in primary human macrophages; however, the underlying mechanism of tamoxifen action remains unknown (50). Although the direct antibacterial effects of tamoxifen against intracellular pathogens have been documented earlier (31), its potential to act as a host-directed therapeutic (HDT) for TB is just beginning to be investigated (40).…”

Section: Discussionmentioning

confidence: 99%

“…The best-known target for tamoxifen is the host ER (40). Additionally, tamoxifen modulates other host pathways, such as autophagy and lysosome function (43, 50). Published data supports the notion that an increase in lysosomal activation by tamoxifen equips the host to control intracellular replication of pathogens such as M. tb (43, 50).…”

Section: Discussionmentioning

confidence: 99%

“…PCR Master mix (PowerUp™ SYBR™ Green Master Mix, Applied Biosystems) was added to each well along with the specific primer pair for each gene. The reactions were then subjected to 35 A model is proposed based on the data obtained from this study and previously published literature (43,50). A comprehensive view of TCS crosstalk was reported previously (8,30).…”

Section: Rna Isolation and Real-time Pcr Analysismentioning

confidence: 95%

See 3 more Smart Citations

Anti-cancer drug Tamoxifen interferes withMycobacterium tuberculosisPhoPR mediated signaling and inhibits mycobacterial growth

Garg,

Pandit,

Malhotra

et al. 2023

Preprint

View full text Add to dashboard Cite

Two-component signaling (TCS) systems empower all bacteria, including intracellular pathogens likeMycobacterium tuberculosis (M. tb)to regulate key pathways governing growth, physiology and virulence. Amongst allM. tbTCS systems, PhoPR and DevRS have been studied extensively for their roles in regulating persistence and virulence. Here, we report that besides its cognate response regulator PhoP, the PhoR sensor kinase displays several non-cognate interactions that augment its role in pathogenesis. We demonstrate that PhoR phosphorylates the DevR response regulator and furthermore, is itself subjected toO-phosphorylation by PknK, a Ser/Thr protein kinase (STPK), connecting TCS pathways with “eukaryotic-like” STPK driven phosphosignaling. This intersection of non-canonical regulatory pathways and the coregulation of PhoP and DevR regulons makeM. tbPhoR a potentially attractive drug target. We rationalized that disruption of PhoPR signaling cascade and the resulting dysregulation may result in decreased virulence ofM. tb. We tested this hypothesis by performing a high-throughput screen for compounds that inhibit autophosphorylation of PhoR sensor kinase. Screening of pharmacologically active, small molecule libraries yielded 11 potential inhibitors, of which one compound, Tamoxifen was able to attenuate PhoR autophosphorylation at micromolar concentrationsin vitroandin vivo. Tamoxifen not only inhibited growth ofMycobacterium bovisBCG in culture but also interrupted PhoPR-mediated downstream signaling. Quantitative expression analysis revealed suppression of target gene,aprAunder acidic conditions. Our findings highlight TCS sensor kinases as promising drug targets and underscore the applicability of clinically relevant anti-cancer drug tamoxifen as a repurposed anti-TB drug.

show abstract

“…A model is proposed based on the data obtained from this study and previously published literature (43, 50). A comprehensive view of TCS crosstalk was reported previously (8, 30).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Rna Isolation and Real-time Pcr Analysismentioning

confidence: 95%

See 2 more Smart Citations

Anti-cancer drug Tamoxifen interferes withMycobacterium tuberculosisPhoPR mediated signaling and inhibits mycobacterial growth

Garg,

Pandit,

Malhotra

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Boland et al. proved that the antitumor agent tamoxifen, although it lacked a direct antimicrobial effect, could produce an anti-TB effect by inducing autophagy rather than targeting its classical estrogen receptor pathway ( 86 ). This finding was further validated in a zebrafish model of TB infection, confirming the HDT potential of tamoxifen.…”

Section: The Candidates Of Hdt For Mtb Treatmentmentioning

confidence: 99%

Host-directed therapy against mycobacterium tuberculosis infections with diabetes mellitus

Zhao,

Fan,

Sun

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

Tuberculosis (TB) is caused by the bacterial pathogen Mycobacterium tuberculosis (MTB) and is one of the principal reasons for mortality and morbidity worldwide. Currently, recommended anti-tuberculosis drugs include isoniazid, rifampicin, ethambutol, and pyrazinamide. TB treatment is lengthy and inflicted with severe side-effects, including reduced patient compliance with treatment and promotion of drug-resistant strains. TB is also prone to other concomitant diseases such as diabetes and HIV. These drug-resistant and complex co-morbid characteristics increase the complexity of treating MTB. Host-directed therapy (HDT), which effectively eliminates MTB and minimizes inflammatory tissue damage, primarily by targeting the immune system, is currently an attractive complementary approach. The drugs used for HDT are repositioned drugs in actual clinical practice with relative safety and efficacy assurance. HDT is a potentially effective therapeutic intervention for the treatment of MTB and diabetic MTB, and can compensate for the shortcomings of current TB therapies, including the reduction of drug resistance and modulation of immune response. Here, we summarize the state-of-the-art roles and mechanisms of HDT in immune modulation and treatment of MTB, with a special focus on the role of HDT in diabetic MTB, to emphasize the potential of HDT in controlling MTB infection.

show abstract

Recognition of Mycobacterium tuberculosis by macrophage Toll-like receptor and its role in autophagy

Wei,

Liu,

Meng

et al. 2024

Inflamm. Res.

View full text Add to dashboard Cite

Repurposing Tamoxifen as Potential Host-Directed Therapeutic for Tuberculosis

Abstract: 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.

Cited by 17 publications

References 97 publications

Anti-cancer drug Tamoxifen interferes withMycobacterium tuberculosisPhoPR mediated signaling and inhibits mycobacterial growth

Anti-cancer drug Tamoxifen interferes withMycobacterium tuberculosisPhoPR mediated signaling and inhibits mycobacterial growth

Host-directed therapy against mycobacterium tuberculosis infections with diabetes mellitus

Recognition of Mycobacterium tuberculosis by macrophage Toll-like receptor and its role in autophagy

Contact Info

Product

Resources

About