A Novel Antiparasitic Compound Kills Ring-Stage Plasmodium falciparum and Retains Activity Against Artemisinin-Resistant Parasites

被引：7

作者：

Clements, Rebecca L. ^{[1
,2
]}

Streva, Vincent ^{[2
]}

Dumoulin, Peter ^{[3
]}

Huang, Weigang ^{[4
]}

Owens, Edward ^{[5
]}

Raj, Dipak K. ^{[7
]}

Burleigh, Barbara ^{[3
]}

Llinas, Manuel ^{[5
,8
]}

Winzeler, Elizabeth A. ^{[6
]}

Zhang, Qisheng ^{[4
]}

Dvorin, Jeffrey D. ^{[2
,9
]}

机构：

[1] Harvard Med Sch, Biol & Biomed Sci, Boston, MA 02115 USA

[2] Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA

[3] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA

[4] Univ N Carolina, Div Chem Biol & Med Chem, Chapel Hill, NC 27515 USA

[5] Penn State Univ, Huck Ctr Malaria Res, University Pk, PA 16802 USA

[6] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA

[7] Brown Univ, Rhode Isl Hosp, Med Sch, Ctr Int Hlth Res, Providence, RI 02903 USA

[8] Penn State Univ, Dept Chem, University Pk, PA USA

[9] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA

来源：

JOURNAL OF INFECTIOUS DISEASES | 2020年 / 221卷 / 06期

基金：

比尔及梅琳达.盖茨基金会; 美国国家卫生研究院;

关键词：

antimalarial; artemisinin resistance; malaria; Plasmodium falciparum; ring-stage survival;

D O I：

10.1093/infdis/jiz534

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Spreading antimalarial resistance threatens effective treatment of malaria, an infectious disease caused by Plasmodium parasites. We identified a compound, BCH070, that inhibits asexual growth of multiple antimalarial-resistant strains of Plasmodium falciparum (half maximal inhibitory concentration [IC50] = 1-2 mu M), suggesting that BCH070 acts via a novel mechanism of action. BCH070 preferentially kills early ring-form trophozoites, and, importantly, equally inhibits ring-stage survival of wild-type and artemisinin-resistant parasites harboring the PfKelch13:C580Y mutation. Metabolomic analysis demonstrates that BCH070 likely targets multiple pathways in the parasite. BCH070 is a promising lead compound for development of new antimalarial combination therapy that retains activity against artemisinin-resistant parasites.

引用

页码：956 / 962

页数：7

共 15 条

[11] Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum [J].

Painter, Heather J. ;

Morrisey, Joanne M. ;

Mather, Michael W. ;

Vaidya, Akhil B. .

NATURE, 2007, 446 (7131) :88-91

[12] Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone [J].

Skinner-Adams, Tina S. ;

Fishers, Gillian M. ;

Riches, Andrew G. ;

Hutt, Oliver E. ;

Jarvis, Karen E. ;

Wilson, Tony ;

von Ltzstein, Mark ;

Chopra, Pradeep ;

Antonova-Koch, Yevgeniya ;

Meister, Stephan ;

Winzeler, Elizabeth A. ;

Clarke, Mary ;

Fidock, David A. ;

Burrows, Jeremy N. ;

Ryan, John H. ;

Andrews, Katherine T. .

COMMUNICATIONS BIOLOGY, 2019, 2 (1)

[13] K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates [J].

Straimer, Judith ;

Gnaedig, Nina F. ;

Witkowski, Benoit ;

Amaratunga, Chanaki ;

Duru, Valentine ;

Ramadani, Arba Pramundita ;

Dacheux, Melanie ;

Khim, Nimol ;

Zhang, Lei ;

Lam, Stephen ;

Gregory, Philip D. ;

Urnov, Fyodor D. ;

Mercereau-Puijalon, Odile ;

Benoit-Vical, Francoise ;

Fairhurst, Rick M. ;

Menard, Didier ;

Fidock, David A. .

SCIENCE, 2015, 347 (6220) :428-431

[14]

WHO, 2018, World Drug Report 2018

[15] CLONAL VIABILITY MEASUREMENTS ON PLASMODIUM-FALCIPARUM TO ASSESS INVITRO SCHIZONTICIDAL ACTIVITY OF LEUPEPTIN, CHLOROQUINE, AND 5-FLUOROOROTATE [J].

YOUNG, RD ;

RATHOD, RK .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1993, 37 (05) :1102-1107

← 1 2 →