A broad analysis of resistance development in the malaria parasite

被引：94

作者：

Corey, Victoria C. ^{[1
]}

Lukens, Amanda K. ^{[2
,3
]}

Istvan, Eva S. ^{[4
]}

Lee, Marcus C. S. ^{[5
]}

Franco, Virginia ^{[6
]}

Magistrado, Pamela ^{[2
]}

Coburn-Flynn, Olivia ^{[5
]}

Sakata-Kato, Tomoyo ^{[2
]}

Fuchs, Olivia ^{[1
]}

Gnadig, Nina F. ^{[5
]}

Goldgof, Greg ^{[1
]}

Linares, Maria ^{[6
]}

Gomez-Lorenzo, Maria G. ^{[6
]}

De Cozar, Cristina ^{[6
]}

Jose Lafuente-Monasterio, Maria ^{[6
]}

Prats, Sara ^{[6
]}

Meister, Stephan ^{[1
]}

Tanaseichuk, Olga ^{[7
]}

Wree, Melanie ^{[1
]}

Zhou, Yingyao ^{[7
]}

Willis, Paul A. ^{[8
]}

Gamo, Francisco-Javier ^{[6
]}

Goldberg, Daniel E. ^{[4
]}

Fidock, David A. ^{[5
]}

Wirth, Dyann F. ^{[2
,3
]}

Winzeler, Elizabeth A. ^{[1
]}

机构：

[1] Univ Calif San Diego, Sch Med, Dept Pediat, 9500 Gilman Dr 0741, La Jolla, CA 92093 USA

[2] Harvard Univ, TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, 665 Huntington Ave, Boston, MA 02115 USA

[3] Broad Inst, Program Infect Dis, 415 Main St, Cambridge, MA 02142 USA

[4] Washington Univ, Sch Med, Dept Med & Microbiol, St Louis, MO 63110 USA

[5] Columbia Univ Coll Phys & Surg, Dept Microbiol & Immunol, 630 W 168th St, New York, NY 10032 USA

[6] GlaxoSmithKline, Malaria DPU, Tres Cantos Med Dev Campus,Severo Ochoa 2, Madrid 28760, Spain

[7] Novartis Res Fdn, Genom Inst, 10675 John J Hopkins Dr, San Diego, CA 92121 USA

[8] Med Malaria Venture, POB 1826,20 Route Prebois, CH-1215 Geneva 15, Switzerland

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

关键词：

PLASMODIUM-FALCIPARUM; ARTEMISININ RESISTANCE; CLINICAL CANDIDATE; ANTIMALARIAL-DRUGS; DISCOVERY; VALIDATION; MUTATIONS; DIVERSITY; INVITRO; SITE;

D O I：

10.1038/ncomms11901

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Microbial resistance to chemotherapy has caused countless deaths where malaria is endemic. Chemotherapy may fail either due to pre-existing resistance or evolution of drug-resistant parasites. Here we use a diverse set of antimalarial compounds to investigate the acquisition of drug resistance and the degree of cross-resistance against common resistance alleles. We assess cross-resistance using a set of 15 parasite lines carrying resistance-conferring alleles in pfatp4, cytochrome bc(1), pfcarl, pfdhod, pfcrt, pfmdr, pfdhfr, cytoplasmic prolyl t-RNA synthetase or hsp90. Subsequently, we assess whether resistant parasites can be obtained after several rounds of drug selection. Twenty-three of the 48 in vitro selections result in resistant parasites, with time to resistance onset ranging from 15 to 300 days. Our data indicate that pre-existing resistance may not be a major hurdle for novel-target antimalarial candidates, and focusing our attention on fast-killing compounds may result in a slower onset of clinical resistance.

引用

页数：9

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