University General - Research Publications

Permanent URI for this collection

http://hdl.handle.net/11343/198003

Filters

2022 1
1
Reset filters

Settings
Statistics
Citations
Author: Creek, Darren × Author: Goodman, Christopher × End date: 2023 × Start date: 2020 ×

Search Results

Now showing 1 - 1 of 1
  • Item
    Thumbnail Image
    Targeting malaria parasites with novel derivatives of azithromycin
    Burns, AL ; Sleebs, BE ; Gancheva, M ; McLean, KT ; Siddiqui, G ; Venter, H ; Beeson, JG ; O'Handley, R ; Creek, DJ ; Ma, S ; Froelich, S ; Goodman, CD ; McFadden, G ; Wilson, DW (FRONTIERS MEDIA SA, 2022-11-30)
    INTRODUCTION: The spread of artemisinin resistant Plasmodium falciparum parasites is of global concern and highlights the need to identify new antimalarials for future treatments. Azithromycin, a macrolide antibiotic used clinically against malaria, kills parasites via two mechanisms: 'delayed death' by inhibiting the bacterium-like ribosomes of the apicoplast, and 'quick-killing' that kills rapidly across the entire blood stage development. METHODS: Here, 22 azithromycin analogues were explored for delayed death and quick-killing activities against P. falciparum (the most virulent human malaria) and P. knowlesi (a monkey parasite that frequently infects humans). RESULTS: Seventeen analogues showed improved quick-killing against both Plasmodium species, with up to 38 to 20-fold higher potency over azithromycin after less than 48 or 28 hours of treatment for P. falciparum and P. knowlesi, respectively. Quick-killing analogues maintained activity throughout the blood stage lifecycle, including ring stages of P. falciparum parasites (<12 hrs treatment) and were >5-fold more selective against P. falciparum than human cells. Isopentenyl pyrophosphate supplemented parasites that lacked an apicoplast were equally sensitive to quick-killing analogues, confirming that the quick killing activity of these drugs was not directed at the apicoplast. Further, activity against the related apicoplast containing parasite Toxoplasma gondii and the gram-positive bacterium Streptococcus pneumoniae did not show improvement over azithromycin, highlighting the specific improvement in antimalarial quick-killing activity. Metabolomic profiling of parasites subjected to the most potent compound showed a build-up of non-haemoglobin derived peptides that was similar to chloroquine, while also exhibiting accumulation of haemoglobin-derived peptides that was absent for chloroquine treatment. DISCUSSION: The azithromycin analogues characterised in this study expand the structural diversity over previously reported quick-killing compounds and provide new starting points to develop azithromycin analogues with quick-killing antimalarial activity.