Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Antibiotic inhibition of the Plasmodium apicoplast decreases haemoglobin degradation and antagonises dihydroartemisinin action

View ORCID ProfileEmily M. Crisafulli, Amanda De Paoli, View ORCID ProfileMadel V. Tutor, View ORCID ProfileGhizal Siddiqui, View ORCID ProfileDarren J. Creek, View ORCID ProfileLeann Tilley, View ORCID ProfileStuart A. Ralph
doi: https://doi.org/10.1101/2021.10.31.466372
Emily M. Crisafulli
1Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, VIC 3052, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Emily M. Crisafulli
Amanda De Paoli
2Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Madel V. Tutor
1Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, VIC 3052, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Madel V. Tutor
Ghizal Siddiqui
2Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ghizal Siddiqui
Darren J. Creek
2Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Darren J. Creek
Leann Tilley
1Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, VIC 3052, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Leann Tilley
Stuart A. Ralph
1Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, VIC 3052, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Stuart A. Ralph
  • For correspondence: saralph@unimelb.edu.au
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

The World Health Organisation (WHO) recommends artemisinin (ART) combinations for treatment of uncomplicated Plasmodium falciparum malaria. Understanding the interaction between co-administered drugs within combination therapies is clinically important to prevent unintended consequences. The WHO guidelines recommend second line treatments that combine artesunate with tetracycline, doxycycline, or clindamycin—antibiotics that target the Plasmodium relict plastid, the apicoplast. In addition, antibiotics can be used simultaneously against other infectious diseases, leading to their inadvertent combination with ARTs. One consequence of apicoplast inhibition is a perturbation to haemoglobin uptake and trafficking—a pathway required for activation of ART derivatives. Here, we show that apicoplast-targeting antibiotics reduce the abundance of the catalyst of ART activation (free haem) in P. falciparum, likely through diminished haemoglobin digestion. We demonstrate antagonism between ART and these antibiotics, suggesting that apicoplast inhibitors reduce ART activation. These data have potential clinical implications due to the reliance on—and widespread use of—both ARTs and these antibiotics in malaria endemic regions.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted November 01, 2021.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Antibiotic inhibition of the Plasmodium apicoplast decreases haemoglobin degradation and antagonises dihydroartemisinin action
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Antibiotic inhibition of the Plasmodium apicoplast decreases haemoglobin degradation and antagonises dihydroartemisinin action
Emily M. Crisafulli, Amanda De Paoli, Madel V. Tutor, Ghizal Siddiqui, Darren J. Creek, Leann Tilley, Stuart A. Ralph
bioRxiv 2021.10.31.466372; doi: https://doi.org/10.1101/2021.10.31.466372
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Antibiotic inhibition of the Plasmodium apicoplast decreases haemoglobin degradation and antagonises dihydroartemisinin action
Emily M. Crisafulli, Amanda De Paoli, Madel V. Tutor, Ghizal Siddiqui, Darren J. Creek, Leann Tilley, Stuart A. Ralph
bioRxiv 2021.10.31.466372; doi: https://doi.org/10.1101/2021.10.31.466372

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Microbiology
Subject Areas
All Articles
  • Animal Behavior and Cognition (4381)
  • Biochemistry (9581)
  • Bioengineering (7086)
  • Bioinformatics (24845)
  • Biophysics (12597)
  • Cancer Biology (9952)
  • Cell Biology (14346)
  • Clinical Trials (138)
  • Developmental Biology (7944)
  • Ecology (12101)
  • Epidemiology (2067)
  • Evolutionary Biology (15984)
  • Genetics (10921)
  • Genomics (14735)
  • Immunology (9869)
  • Microbiology (23645)
  • Molecular Biology (9477)
  • Neuroscience (50838)
  • Paleontology (369)
  • Pathology (1539)
  • Pharmacology and Toxicology (2681)
  • Physiology (4013)
  • Plant Biology (8655)
  • Scientific Communication and Education (1508)
  • Synthetic Biology (2391)
  • Systems Biology (6427)
  • Zoology (1346)