RT Journal Article SR Electronic T1 Antibiotic inhibition of the Plasmodium apicoplast decreases haemoglobin degradation and antagonises dihydroartemisinin action JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.10.31.466372 DO 10.1101/2021.10.31.466372 A1 Emily M. Crisafulli A1 Amanda De Paoli A1 Madel V. Tutor A1 Ghizal Siddiqui A1 Darren J. Creek A1 Leann Tilley A1 Stuart A. Ralph YR 2021 UL http://biorxiv.org/content/early/2021/11/01/2021.10.31.466372.abstract AB 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 StatementThe authors have declared no competing interest.