Mode of action of quinoline antimalarial drugs in red blood cells infected by Plasmodium falciparum revealed in vivo

Author:

Kapishnikov SergeyORCID,Staalsø Trine,Yang Yang,Lee Jiwoong,Pérez-Berná Ana J.,Pereiro EvaORCID,Yang Yang,Werner Stephan,Guttmann PeterORCID,Leiserowitz Leslie,Als-Nielsen Jens

Abstract

The most widely used antimalarial drugs belong to the quinoline family. Their mode of action has not been characterized at the molecular level in vivo. We report the in vivo mode of action of a bromo analog of the drug chloroquine in rapidly frozen Plasmodium falciparum-infected red blood cells. The Plasmodium parasite digests hemoglobin, liberating the heme as a byproduct, toxic to the parasite. It is detoxified by crystallization into inert hemozoin within the parasitic digestive vacuole. By mapping such infected red blood cells with nondestructive X-ray microscopy, we observe that bromoquine caps hemozoin crystals. The measured crystal surface coverage is sufficient to inhibit further hemozoin crystal growth, thereby sabotaging heme detoxification. Moreover, we find that bromoquine accumulates in the digestive vacuole, reaching submillimolar concentration, 1,000-fold more than that of the drug in the culture medium. Such a dramatic increase in bromoquine concentration enhances the drug’s efficiency in depriving heme from docking onto the hemozoin crystal surface. Based on direct observation of bromoquine distribution in the digestive vacuole and at its membrane surface, we deduce that the excess bromoquine forms a complex with the remaining heme deprived from crystallization. This complex is driven toward the digestive vacuole membrane, increasing the chances of membrane puncture and spillage of heme into the interior of the parasite.

Funder

Carlsbergfondet

Novo Nordisk

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Reference39 articles.

1. P. S. Callaghan , P. D. Roepe , “The biochemistry of quinoline antimalarial drug resistance” in Handbook of Antimicrobial Resistance, M. Gotte , A. Berghuis , G. Matlashewski , M. Wainberg , D. Sheppard , S. N. York , N. York , Eds. (Springer, New York, 2014), pp. 1–20.

2. R. M. Fairhurst , A. M. Dondorp , Artemisinin-resistant Plasmodium falciparum malaria. Microbiol. Spectr. 4 (2016).

3. How to defuse malaria’s ticking time bomb;Maxmen;Nature,2018

4. Unraveling heme detoxification in the malaria parasite by in situ correlative X-ray fluorescence microscopy and soft X-ray tomography

5. Quinolines and artemisinin: Chemistry, biology and history;Bray;Curr. Top. Microbiol. Immunol.,2005

全球学者库

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"全球学者库"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前全球学者库共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2023 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3