Domperidone Inhibits <i>Clostridium botulinum</i> C2 Toxin and <i>Bordetella pertussis</i> Toxin
<i>Bordetella pertussis</i> toxin (PT) and <i>Clostridium botulinum</i> C2 toxin are ADP-ribosylating toxins causing severe diseases in humans and animals. They share a common translocation mechanism requiring the cellular chaperones Hsp90 and Hsp70, cyclophilins, and FK506-b...
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| Format: | Article |
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MDPI AG
2023-06-01
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| Series: | Toxins |
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| Online Access: | https://www.mdpi.com/2072-6651/15/7/412 |
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| author | Jinfang Jia Maria Braune-Yan Stefanie Lietz Mary Wahba Arto T. Pulliainen Holger Barth Katharina Ernst |
| author_facet | Jinfang Jia Maria Braune-Yan Stefanie Lietz Mary Wahba Arto T. Pulliainen Holger Barth Katharina Ernst |
| author_sort | Jinfang Jia |
| collection | DOAJ |
| description | <i>Bordetella pertussis</i> toxin (PT) and <i>Clostridium botulinum</i> C2 toxin are ADP-ribosylating toxins causing severe diseases in humans and animals. They share a common translocation mechanism requiring the cellular chaperones Hsp90 and Hsp70, cyclophilins, and FK506-binding proteins to transport the toxins’ enzyme subunits into the cytosol. Inhibitors of chaperone activities have been shown to reduce the amount of transported enzyme subunits into the cytosol of cells, thus protecting cells from intoxication by these toxins. Recently, domperidone, an approved dopamine receptor antagonist drug, was found to inhibit Hsp70 activity. Since Hsp70 is required for cellular toxin uptake, we hypothesized that domperidone also protects cells from intoxication with PT and C2. The inhibition of intoxication by domperidone was demonstrated by analyzing the ADP-ribosylation status of the toxins’ specific substrates. Domperidone had no inhibitory effect on the receptor-binding or enzyme activity of the toxins, but it inhibited the pH-driven membrane translocation of the enzyme subunit of the C2 toxin and reduced the amount of PTS1 in cells. Taken together, our results indicate that domperidone is a potent inhibitor of PT and C2 toxins in cells and therefore might have therapeutic potential by repurposing domperidone to treat diseases caused by bacterial toxins that require Hsp70 for their cellular uptake. |
| first_indexed | 2024-03-11T00:35:11Z |
| format | Article |
| id | doaj.art-6097fc02ea9f40d0bdb38aa14beaddcb |
| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-03-11T00:35:11Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-6097fc02ea9f40d0bdb38aa14beaddcb2023-11-18T21:37:49ZengMDPI AGToxins2072-66512023-06-0115741210.3390/toxins15070412Domperidone Inhibits <i>Clostridium botulinum</i> C2 Toxin and <i>Bordetella pertussis</i> ToxinJinfang Jia0Maria Braune-Yan1Stefanie Lietz2Mary Wahba3Arto T. Pulliainen4Holger Barth5Katharina Ernst6Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center, 89081 Ulm, GermanyInstitute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center, 89081 Ulm, GermanyInstitute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center, 89081 Ulm, GermanyInstitute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center, 89081 Ulm, GermanyInstitute of Biomedicine, University of Turku, FI-20520 Turku, FinlandInstitute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center, 89081 Ulm, GermanyInstitute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center, 89081 Ulm, Germany<i>Bordetella pertussis</i> toxin (PT) and <i>Clostridium botulinum</i> C2 toxin are ADP-ribosylating toxins causing severe diseases in humans and animals. They share a common translocation mechanism requiring the cellular chaperones Hsp90 and Hsp70, cyclophilins, and FK506-binding proteins to transport the toxins’ enzyme subunits into the cytosol. Inhibitors of chaperone activities have been shown to reduce the amount of transported enzyme subunits into the cytosol of cells, thus protecting cells from intoxication by these toxins. Recently, domperidone, an approved dopamine receptor antagonist drug, was found to inhibit Hsp70 activity. Since Hsp70 is required for cellular toxin uptake, we hypothesized that domperidone also protects cells from intoxication with PT and C2. The inhibition of intoxication by domperidone was demonstrated by analyzing the ADP-ribosylation status of the toxins’ specific substrates. Domperidone had no inhibitory effect on the receptor-binding or enzyme activity of the toxins, but it inhibited the pH-driven membrane translocation of the enzyme subunit of the C2 toxin and reduced the amount of PTS1 in cells. Taken together, our results indicate that domperidone is a potent inhibitor of PT and C2 toxins in cells and therefore might have therapeutic potential by repurposing domperidone to treat diseases caused by bacterial toxins that require Hsp70 for their cellular uptake.https://www.mdpi.com/2072-6651/15/7/412AB-type protein toxinADP-ribosylating toxinpertussis toxinwhooping coughC2 toxinmembrane transport |
| spellingShingle | Jinfang Jia Maria Braune-Yan Stefanie Lietz Mary Wahba Arto T. Pulliainen Holger Barth Katharina Ernst Domperidone Inhibits <i>Clostridium botulinum</i> C2 Toxin and <i>Bordetella pertussis</i> Toxin Toxins AB-type protein toxin ADP-ribosylating toxin pertussis toxin whooping cough C2 toxin membrane transport |
| title | Domperidone Inhibits <i>Clostridium botulinum</i> C2 Toxin and <i>Bordetella pertussis</i> Toxin |
| title_full | Domperidone Inhibits <i>Clostridium botulinum</i> C2 Toxin and <i>Bordetella pertussis</i> Toxin |
| title_fullStr | Domperidone Inhibits <i>Clostridium botulinum</i> C2 Toxin and <i>Bordetella pertussis</i> Toxin |
| title_full_unstemmed | Domperidone Inhibits <i>Clostridium botulinum</i> C2 Toxin and <i>Bordetella pertussis</i> Toxin |
| title_short | Domperidone Inhibits <i>Clostridium botulinum</i> C2 Toxin and <i>Bordetella pertussis</i> Toxin |
| title_sort | domperidone inhibits i clostridium botulinum i c2 toxin and i bordetella pertussis i toxin |
| topic | AB-type protein toxin ADP-ribosylating toxin pertussis toxin whooping cough C2 toxin membrane transport |
| url | https://www.mdpi.com/2072-6651/15/7/412 |
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