Summary of Study ST002309

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

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

Study ID	ST002309
Study Title	Targeting malaria parasites with novel derivatives of azithromycin
Study 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
Submit Date	2022-10-04
Raw Data Available	Yes
Raw Data File Type(s)	raw(Thermo)
Analysis Type Detail	LC-MS
Release Date	2022-10-25
Release Version	1

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Treatment:

Treatment ID:	TR002407
Treatment Summary:	For metabolomics experiments, two 150 mL flasks at 6% haematocrit containing tightly synchronised parasites 28-34 hrs post-invasion (5-6 hrs rupture window), were harvested via magnet purification (Miltenyi Biotech). Infected RBC density was quantitated by flow cytometry (Tham et al., 2010) and 2 mL of 3x 107 parasites were added into the wells of 24 well microtiter plates. Parasites were incubated for 1 hrs at 37o C to stabilise the culture. Following this initial incubation, 5x IC50 of the azithromycin analogue C1 and control drugs chloroquine, dihydroartemisinin (DHA) and azithromycin were added and incubated for 2 hrs.

Treatment ID:

TR002407

Treatment Summary:

For metabolomics experiments, two 150 mL flasks at 6% haematocrit containing tightly synchronised parasites 28-34 hrs post-invasion (5-6 hrs rupture window), were harvested via magnet purification (Miltenyi Biotech). Infected RBC density was quantitated by flow cytometry (Tham et al., 2010) and 2 mL of 3x 107 parasites were added into the wells of 24 well microtiter plates. Parasites were incubated for 1 hrs at 37o C to stabilise the culture. Following this initial incubation, 5x IC50 of the azithromycin analogue C1 and control drugs chloroquine, dihydroartemisinin (DHA) and azithromycin were added and incubated for 2 hrs.