Summary of project PR001480
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001480. The data can be accessed directly via it's Project DOI: 10.21228/M8DT4D This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR001480 |
| Project DOI: | doi: 10.21228/M8DT4D |
| Project Title: | Targeting malaria parasites with novel derivatives of azithromycin |
| Project Summary: | 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. 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). 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. Lead analogues had limited activity against the related parasite Toxoplasma gondii and were >5-fold more selective against malaria than human cells. Quick-killing analogues maintained activity throughout the blood stage lifecycle including ring stages of P. falciparum parasites (<12 hrs treatment). 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. Metabolomic profiling of parasites subjected to the lead analogue revealed a similar profile to chloroquine treatment, suggesting that the food-vacuole is a likely target of this drugs activity. The azithromycin analogues characterised in this study expanded the structural diversity over previously reported quick-killing compounds and provide new starting points to develop azithromycin analogues with quick-killing antimalarial activity. |
| Institute: | Monash University |
| Last Name: | Siddiqui |
| First Name: | Ghizal |
| Address: | 381 Royal Parade, Parkville, Melbourne, Victoria, 3052, Australia |
| Email: | ghizal.siddiqui@monash.edu |
| Phone: | 99039282 |
Summary of all studies in project PR001480
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST002309 | Targeting malaria parasites with novel derivatives of azithromycin | Plasmodium falciparum | Monash University | MS | 2022-10-25 | 1 | 6 | Uploaded data (277.5M)* |
