Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections
| Autor: | Matthias T. Heemskerk, Cornelis J. Korbee, Louis Wilson, C. Carvalho dos Santos, Mariëlle C. Haks, Tom H. M. Ottenhoff, Karin Dijkman, Frank A. W. Verreck, S. Q. van Veen, I. F. Gordijn, Frank Vrieling, C. G. Engele, J. J. Esselink, Kimberley V. Walburg |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Science
medicine.medical_treatment Antitubercular Agents Drug Evaluation Preclinical Microbial Sensitivity Tests Biology Pharmacology Models Biological Article Cell Line Small Molecule Libraries Mycobacterium tuberculosis Pimozide Phagosomes Autophagy medicine Humans Tuberculosis Diphenylbutylpiperidine Fluspirilene Multidisciplinary Dose-Response Relationship Drug Drug Repositioning High-throughput screening Salmonella enterica Antimicrobial responses Immunotherapy biology.organism_classification Anti-Bacterial Agents High-Throughput Screening Assays Innate immune cells Salmonella Infections Infectious diseases Medicine Lysosomes Intracellular Antipsychotic Agents medicine.drug |
| Zdroj: | Scientific Reports, Vol 11, Iss 1, Pp 1-18 (2021) Scientific Reports, 11(1). NATURE PORTFOLIO Scientific Reports |
| Popis: | The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide’s and Fluspirilene’s efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms. |
| Databáze: | OpenAIRE |
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