Retargeting a safe and inexpensive antibiotic to quickly kill malaria parasites in two different ways.

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1. Please give a summary of your research.

If you were developing next-generation drugs to combat drug-resistant malaria, a parasitic disease that kills >400,000 children and puts at risk >100 million pregnancies every year [1], what would you be looking for?

A drug that rapidly kills disease-causing parasites living inside human red blood cells would be a priority.

·     I discovered that the safe and widely used antibiotic azithromycin has broad ‘quick-killing’ activity against blood stage malaria parasites – inhibiting red blood cell invasion (People’s Choice Award entry) and stopping growth and multiplication inside red cells [2, 3].

What about a drug where resistance develops slowly or not at all?

·     In addition to quick-killing activity, azithromycin has a ‘slow-killing’ (death in 5 days) antimalarial action that targets special proteins obtained from an ancient bacteria [4]. Optimising azithromycin to act through two independent mechanisms of action, one that kills quickly and one that ‘mops-up’ break through parasites, would force the malaria parasite to mutate twice to become resistant, significantly reducing the risk of resistance developing [5].

A long-lasting drug with long-term efficacy to improve combination therapies.

·     Azithromycin is maintained at an effective concentration in blood for weeks.

A drug that is potent at low concentrations.

·     We have identified azithromycin analogues that kill parasites through both quick and slow killing activities [2] at concentrations well below those safely achievable for azithromycin in the blood.

A drug that is safe and inexpensive so children and pregnant women in developing countries can access treatment.

·     Azithromycin has >25 years of clinical use in children and pregnant women. Azithromycin is inexpensive and has proven tractability to modification [6], providing a cost-effective antimalarial development strategy.

I aim to retarget azithromycin as a next-generation antimalarial with dual-modality that will maximise clinical benefits of combination therapies [7, 8] and minimise drug resistance.

2. Please include any additional details you would like to share

1.        WHO: World Malaria Report 2016. Geneva, World Health Organization: WHO; 2016.

2.        Wilson DW, Goodman CD, Sleebs BE, Weiss GE, de Jong NW, Angrisano F, Langer C, Baum J, Crabb BS, Gilson PR, et al: Macrolides rapidly inhibit red blood cell invasion by the human malaria parasite, Plasmodium falciparum. BMC Biol 2015, 13:52.

3.        Boyle MJ, Wilson DW, Richards JS, Riglar DT, Tetteh KK, Conway DJ, Ralph SA, Baum J, Beeson JG: Isolation of viable Plasmodium falciparum merozoites to define erythrocyte invasion events and advance vaccine and drug development. Proc Natl Acad Sci U S A 2010, 107:14378-14383.

4.        Sidhu AB, Sun Q, Nkrumah LJ, Dunne MW, Sacchettini JC, Fidock DA: In vitro efficacy, resistance selection, and structural modeling studies implicate the malarial parasite apicoplast as the target of azithromycin. J Biol Chem 2007, 282:2494-2504.

5.        Hastings I: How artemisinin-containing combination therapies slow the spread of antimalarial drug resistance. Trends Parasitol 2011, 27:67-72.

6.        Peric M, Fajdetic A, Rupcic R, Alihodzic S, Ziher D, Bukvic Krajacic M, Smith KS, Ivezic-Schonfeld Z, Padovan J, Landek G, et al: Antimalarial activity of 9a-N substituted 15-membered azalides with improved in vitro and in vivo activity over azithromycin. J Med Chem 2012, 55:1389-1401.

7.        Friesen J, Silvie O, Putrianti ED, Hafalla JC, Matuschewski K, Borrmann S: Natural immunization against malaria: causal prophylaxis with antibiotics. Sci Transl Med 2010, 2:40ra49.

8.        Shimizu S, Osada Y, Kanazawa T, Tanaka Y, Arai M: Suppressive effect of azithromycin on Plasmodium berghei mosquito stage development and apicoplast replication. Malar J 2010, 9:73.

Comments

1
Michelle Boyle
over 2 years ago

Such an exciting and important project!

Image1470371285?1470371285
Round: External Judging
Category: People's Choice Award

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