Dataset Information

Targeting malaria parasites with novel derivatives of azithromycin.

ABSTRACT:

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.

SUBMITTER: Burns AL

PROVIDER: S-EPMC9748569 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Targeting malaria parasites with novel derivatives of azithromycin.

Burns Amy L AL Sleebs Brad E BE Gancheva Maria M McLean Kimberley T KT Siddiqui Ghizal G Venter Henrietta H Beeson James G JG O'Handley Ryan R Creek Darren J DJ Ma Shutao S Frölich Sonja S Goodman Christopher D CD McFadden Geoffrey I GI Wilson Danny W DW

Frontiers in cellular and infection microbiology 20221130

<h4>Introduction</h4>The spread of artemisinin resistant <i>Plasmodium falciparum</i> 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 <i>via</i> 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.<h4>Methods</h4>Here, 22 azithromy ...[more]

PMID: 36530422

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Project description:Malaria, a parasitic disease caused by Plasmodium spp. and transmitted by Anopheles mosquitoes, remains a major global health issue, with an estimated 249 million cases and 608,000 deaths in 2022. Rapid and accurate diagnosis and treatment are crucial for malaria control and elimination. However, limited access to sensitive molecular tests means that microscopic examination and rapid diagnostic tests (RDT) are the most used methods in endemic areas, despite their lower diagnostic accuracy. Therefore, there is a need for developing sensitive, simple, accurate, and rapid diagnostic tools suitable for field conditions. Herein, we aimed to explore the potential of the enzymatic recombinase amplification assay (ERA® Technology) as a remote laboratory test by evaluating and validating the GENEYE® ERA Plasmodium detection kit in Brazilian endemic areas. A cross-sectional cohort study was conducted between June and August of 2023 in the Brazilian Amazon. The study enrolled 323 participants residing in three malaria-affected regions: Cruzeiro do Sul and Mâncio Lima (Acre State) and Guajará (Amazonas State). The participants were tested for malaria by microscopy, rapid diagnostic tests (RDT), nested PCR (nPCR), quantitative real-time PCR (qPCR), and ERA. The sensitivity, specificity, and predictive values were assessed using nPCR as a gold standard. Plasmodium prevalence was 21.7%, 18.8%, 19.2%, 21.7%, and 21.7% by nPCR, microscopy, RDT, qPCR, and ERA respectively. Using nPCR as the standard, qPCR, and ERA showed a sensitivity of 100%. In comparison, microscopy and RDT showed a sensitivity of 87.1% and 88.6%, a negative predictive value (NPV) of 96.56 and 96.93, and kappa values of 0.91 and 0.92, respectively. For Plasmodium falciparum, the sensitivity of qPCR and ERA was 100% while the sensitivity of microscopy and RDT was 96.9% and 93.7%, and the NPV was 99.66 and 99.32, respectively. For Plasmodium vivax, only ERA showed the same sensitivity of nPCR. The sensitivity, NPV, and kappa values were 78.85%, 97.27, and 0.87 for qPCR and microscopy, and 84.21%, 97.94, and 0.9 for RDT. The data presented here show that the GENEYE® ERA Plasmodium detection kit offers a promising alternative to traditional malaria diagnostic methods. Its high sensitivity, specificity, fast processing time, and operational simplicity position it as a valuable point-of-care diagnostic tool, particularly in resource-limited and remote malaria-endemic areas. KEY POINTS: • GENEYE® ERA kit detects Plasmodium in under 25 min, no DNA purification needed. • The kit matches or exceeds the compared methods in sensitivity and specificity. • The kit is suitable for accurate testing in low-infrastructure, point-of-care settings.

Dataset Information

Targeting malaria parasites with novel derivatives of azithromycin.

Introduction

Methods

Results

Discussion

Publications

Targeting malaria parasites with novel derivatives of azithromycin.

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