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• Thompson, Andrew M.; Dal, Nils-Jørgen; Boldrin, Francesca; Rodriguez, Noelia Alonso; Schäfer, Gabriela & Johann, Kerstin [Show all 14 contributors for this article] (2026). New antitubercular pretomanid analogues as potent payloads in polymeric micelles: Leveraging zebrafish assays to accelerate lead optimisation. European Journal of Medicinal Chemistry. ISSN 0223-5234. 307. doi: 10.1016/j.ejmech.2026.118622. Full text in Research Archive
• Cioetto-Mazzabò, Laura; Boldrin, Francesca; Beauvineau, Claire; Speth, Martin Tobias; Marina, Alberto & Namouchi, Amine [Show all 17 contributors for this article] (2023). SigH stress response mediates killing of Mycobacterium tuberculosis by activating nitronaphthofuran prodrugs via induction of Mrx2 expression. Nucleic Acids Research (NAR). ISSN 0305-1048. 51(1), p. 144–165. doi: 10.1093/nar/gkac1173. Full text in Research Archive Show summary

  Abstract The emergence of drug-resistant Mycobacterium tuberculosis strains highlights the need to discover anti-tuberculosis drugs with novel mechanisms of action. Here we discovered a mycobactericidal strategy based on the prodrug activation of selected chemical derivatives classified as nitronaphthofurans (nNFs) mediated by the coordinated action of the sigH and mrx2 genes. The transcription factor SigH is a key regulator of an extensive transcriptional network that responds to oxidative, nitrosative, and heat stresses in M. tuberculosis. The nNF action induced the SigH stress response which in turn induced the mrx2 overexpression. The nitroreductase Mrx2 was found to activate nNF prodrugs, killing replicating, non-replicating and intracellular forms of M. tuberculosis. Analysis of SigH DNA sequences obtained from spontaneous nNF-resistant M. tuberculosis mutants suggests disruption of SigH binding to the mrx2 promoter site and/or RNA polymerase core, likely promoting the observed loss of transcriptional control over Mrx2. Mutations found in mrx2 lead to structural defects in the thioredoxin fold of the Mrx2 protein, significantly impairing the activity of the Mrx2 enzyme against nNFs. Altogether, our work brings out the SigH/Mrx2 stress response pathway as a promising target for future drug discovery programs.

• Dal, Nils-Jørgen Knudsen; Speth, Martin Tobias; Johann, Kerstin; Barz, Matthias; Beauvineau, Claire & Wohlmann, Jens [Show all 10 contributors for this article] (2022). The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds. Disease Models and Mechanisms. ISSN 1754-8403. 15(1). doi: 10.1242/dmm.049147. Full text in Research Archive Show summary

  ABSTRACT With the increasing emergence of drug-resistant Mycobacterium tuberculosis strains, new and effective antibiotics against tuberculosis (TB) are urgently needed. However, the high frequency of poorly water-soluble compounds among hits in high-throughput drug screening campaigns is a major obstacle in drug discovery. Moreover, in vivo testing using conventional animal TB models, such as mice, is time consuming and costly, and represents a major bottleneck in lead compound discovery and development. Here, we report the use of the zebrafish embryo TB model for evaluating the in vivo toxicity and efficacy of five poorly water-soluble nitronaphthofuran derivatives, which were recently identified as possessing anti-TB activity in vitro. To aid solubilization, compounds were formulated in biocompatible polymeric micelles (PMs). Three of the five PM-formulated nitronaphthofuran derivatives showed low toxicity in vivo, significantly reduced bacterial burden and improved survival in infected zebrafish embryos. We propose the zebrafish embryo TB-model as a quick and sensitive tool for evaluating the in vivo toxicity and efficacy of new anti-TB compounds during early stages of drug development. Thus, this model is well suited for pinpointing promising compounds for further development.

• Kocere, Agnese; Resseguier, Julien; Wohlmann, Jens; Skjeldal, Frode Miltzow; Khan, Shanawaz & Speth, Martin [Show all 14 contributors for this article] (2020). Real-time imaging of polymersome nanoparticles in zebrafish embryos engrafted with melanoma cancer cells: Localization, toxicity and treatment analysis. EBioMedicine. 58, p. 1–12. doi: 10.1016/j.ebiom.2020.102902. Full text in Research Archive Show summary

  Background The developing zebrafish is an emerging tool in nanomedicine, allowing non-invasive live imaging of the whole animal at higher resolution than is possible in the more commonly used mouse models. In addition, several transgenic fish lines are available endowed with selected cell types expressing fluorescent proteins; this allows nanoparticles to be visualized together with host cells. Methods Here, we introduce the zebrafish neural tube as a robust injection site for cancer cells, excellently suited for high resolution imaging. We use light and electron microscopy to evaluate cancer growth and to follow the fate of intravenously injected nanoparticles. Findings Fluorescently labelled mouse melanoma B16 cells, when injected into this structure proliferated rapidly and stimulated angiogenesis of new vessels. In addition, macrophages, but not neutrophils, selectively accumulated in the tumour region. When injected intravenously, nanoparticles made of Cy5-labelled poly(ethylene glycol)-block-poly(2-(diisopropyl amino) ethyl methacrylate) (PEG-PDPA) selectively accumulated in the neural tube cancer region and were seen in individual cancer cells and tumour associated macrophages. Moreover, when doxorubicin was released from PEG-PDPA, in a pH dependant manner, these nanoparticles could strongly reduce toxicity and improve the treatment outcome compared to the free drug in zebrafish xenotransplanted with mouse melanoma B16 or human derived melanoma cells. Interpretation The zebrafish has the potential of becoming an important intermediate step, before the mouse model, for testing nanomedicines against patient-derived cancer cells.

• Müller, Elisabeth; Speth, Martin; Christopoulos, Panagiotis; Lunde, Anna; Avdagic, Ajna & Øynebråten, Inger [Show all 7 contributors for this article] (2018). Both type I and type II interferons can activate antitumor M1 macrophages when combined with TLR stimulation. Frontiers in Immunology. 9, p. 1–16. doi: 10.3389/fimmu.2018.02520. Full text in Research Archive Show summary

  Triggering or enhancing antitumor activity of tumor-associated macrophages is an attractive strategy for cancer treatment. We have previously shown that the cytokine interferon-γ (IFN-γ), a type II IFN, could synergize with toll-like receptor (TLR) agonists for induction of antitumor M1 macrophages. However, the toxicity of IFN-γ limits its clinical use. Here, we investigated whether the less toxic type I IFNs, IFN-α, and IFN-β, could potentially replace IFN-γ for induction of antitumor M1 macrophages. We measured in vitro the ability of type I and II IFNs to synergize with TLR agonists for transcription of inducible nitric oxide synthase (iNOS) mRNA and secretion of nitric oxide (NO) by mouse bone marrow-derived macrophages (BMDMs). An in vitro growth inhibition assay was used to measure both cytotoxic and cytostatic activity of activated macrophages against Lewis lung carcinoma (LLC) cancer cells. We found that both type I and II IFNs could synergize with TLR agonists in inducing macrophage-mediated inhibition of cancer cell growth, which was dependent on NO. The ability of high dose lipopolysaccharide (LPS) to induce tumoricidal activity in macrophages in the absence of IFN-γ was shown to depend on induction of autocrine type I IFNs. Antitumor M1 macrophages could also be generated in the absence of IFN-γ by a combination of two TLR ligands when using the TLR3 agonist poly(I:C) which induces autocrine type I IFNs. Finally, we show that encapsulation of poly(I:C) into nanoparticles improved its potency to induce M1 macrophages up to 100-fold. This study reveals the potential of type I IFNs for activation of antitumor macrophages and indicates new avenues for cancer immunotherapy based on type I IFN signaling, including combination of TLR agonists.

• Müller, Elisabeth; Christopoulos, Panagiotis; Halder, Sanjib; Lunde, Anna; Beraki, Kahsai & Speth, Martin [Show all 8 contributors for this article] (2017). Toll-like receptor ligands and interferon-gamma synergize for induction of antitumor M1 macrophages. Frontiers in Immunology. 8. doi: 10.3389/fimmu.2017.01383. Full text in Research Archive Show summary

  Tumor-associated macrophages may either promote or suppress tumor growth depending on their activation status. Interferon-γ (IFN-γ) has been identified as a key factor for inducing tumoricidal M1 phenotype in macrophages. However, it remains unclear whether IFN-γ is sufficient or if additional stimuli are required. Here, we tested IFN-γ and a panel of toll-like receptor (TLR) agonists for the ability to activate murine macrophages toward a tumoricidal M1 phenotype. The following TLR ligands were used: TLR1/TLR2 agonist Pam3CSK4, TLR2/TLR6 agonist lipotechoic acid, TLR3 agonist poly(I:C), TLR4 agonist lipopolysaccharide (LPS), TLR5 agonist flagellin, TLR7 agonist CL264, and TLR9 agonist CpG. We used an in vitro growth inhibition assay to measure both cytotoxic and cytostatic activity of mouse macrophages against Lewis lung carcinoma (LLC) and MOPC315 plasmacytoma tumor cells. Production of nitric oxide (NO) and cytokines by activated macrophages was quantified. We found that IFN-γ alone was not able to render macrophages tumoricidal. Similarly, macrophage activation with single TLR agonists was inefficient. In sharp contrast, IFN-γ was shown to synergize with TLR agonists for induction of macrophage tumoricidal activity and production of both NO and pro-inflammatory cytokines (TNF-α, IL-12p40, and IL-12p70). Furthermore, IFN-γ was shown to suppress macrophage IL-10 secretion induced by TLR agonists. NO production was necessary for macrophage tumoricidal activity. We conclude that two signals from the microenvironment are required for optimal induction of antitumor M1 macrophage phenotype. Combination treatment with IFN-γ and TLR agonists may offer new avenues for macrophage-based cancer immunotherapy.

• Speth, Martin; Repnik, Urska; Müller, Elisabeth; Spanier, Julia; Kalinke, Ulrich & Corthay, Alexandre [Show all 7 contributors for this article] (2017). Poly(I:C)-Encapsulating Nanoparticles Enhance Innate Immune Responses to the Tuberculosis Vaccine Bacille Calmette-Guerin (BCG) via Synergistic Activation of Innate Immune Receptors. Molecular Pharmaceutics. ISSN 1543-8384. 14(11), p. 4098–4112. doi: 10.1021/acs.molpharmaceut.7b00795. Full text in Research Archive
• Løvmo, Signe Dille; Speth, Martin; Repnik, Urska; Koppang, Erling Olaf; Griffiths, Gareth Wyn & Hildahl, Jon Paul (2017). Translocation of nanoparticles and Mycobacterium marinum across the intestinal epithelium in zebrafish and the role of the mucosal immune system. Developmental and Comparative Immunology. ISSN 0145-305X. 67, p. 508–518. doi: 10.1016/j.dci.2016.06.016. Full text in Research Archive
• Repnik, Urska; Distefano, Marita Borg; Speth, Martin; NG, Matthew Yoke Wui; Progida, Cinzia & Hoflack, Bernard [Show all 8 contributors for this article] (2017). L-leucyl-L-leucine methyl ester does not release cysteine cathepsins to the cytosol but inactivates them in transiently permeabilized lysosomes. Journal of Cell Science. ISSN 0021-9533. 130(18), p. 3124–3140. doi: 10.1242/jcs.204529. Full text in Research Archive
• Vibe, Carina Beatrice; Fenaroli, Federico; Pires, David; Wilson, Steven Ray Haakon; Bogoeva, Vanya & Kalluru, Raja Sab [Show all 10 contributors for this article] (2016). Thioridazine in PLGA nanoparticles reduces toxicity and improves rifampicin therapy against mycobacterial infection in zebrafish. Nanotoxicology. ISSN 1743-5390. 10(6), p. 680–688. doi: 10.3109/17435390.2015.1107146. Full text in Research Archive
• Evensen, Lasse; Johansen, Patrick Lie; Koster, Gerbrand; Zhu, Kaizheng; Herfindal, Lars & Speth, Martin [Show all 14 contributors for this article] (2016). Zebrafish as a model system for characterization of nanoparticles against cancer. Nanoscale. ISSN 2040-3364. 8(2), p. 862–877. doi: 10.1039/c5nr07289a. Full text in Research Archive
• Speth, Martin; Repnik, Urska & Griffiths, Gareth Wyn (2016). Layer-by-layer nanocoating of live Bacille-Calmette-Guérin mycobacteria with poly(I:C) and chitosan enhances pro-inflammatory activation and bactericidal capacity in murine macrophages. Biomaterials. ISSN 0142-9612. 111, p. 1–12. doi: 10.1016/j.biomaterials.2016.09.027. Full text in Research Archive
• Kavaliauskis, Arturas; Arnemo, Marianne; Speth, Martin; Lagos, Leidy; Rishovd, Anne-Lise & Estepa, Amparo [Show all 8 contributors for this article] (2016). Protective effect of a recombinant VHSV-G vaccine using poly(I: C) loaded nanoparticles as an adjuvant in zebrafish (Danio rerio) infection model. Developmental and Comparative Immunology. ISSN 0145-305X. 61, p. 248–257. doi: 10.1016/j.dci.2016.04.010. Full text in Research Archive
• Kavaliauskis, Arturas; Arnemo, Marianne; Sung-Hyun, Kim; Ulanova, Lilia; Speth, Martin & Novoa, Beatriz [Show all 10 contributors for this article] (2015). Use of poly(I:C) stabilized with chitosan as a vaccine-adjuvant against viral hemorrhagic septicemia virus infection in zebrafish. Zebrafish. ISSN 1545-8547. 12(6), p. 421–431. doi: 10.1089/zeb.2015.1126. Full text in Research Archive
• Speth, Martin; Kreibich, Claus D; Amdam, Gro Vang & Münch, Daniel (2015). Aging- and task-related resilience decline is linked to food responsiveness in highly social honey bees. Experimental Gerontology. ISSN 0531-5565. 65, p. 46–52. doi: 10.1016/j.exger.2015.03.006. Full text in Research Archive

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• Speth, Martin; Münch, Daniel & Amdam, Gro Vang (2010). Nutrient-sensing, brain nutritional status and survival in the honey bee (Apis mellifera). Full text in Research Archive

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