Dual action antifungal small molecule modulates multidrug efflux and TOR signaling.
Dual action antifungal small molecule modulates multidrug efflux and TOR signaling.
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DOI：
10.1038/nchembio.2165
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发表时间：
2016-10
影响因子：
14.8
通讯作者：
Cowen, Leah E.
中科院分区：
文献类型：
--
作者：
Shekhar-Guturja, Tanvi;Gunaherath, G. M. Kamal B.;Wijeratne, E. M. Kithsiri;Lambert, Jean-Philippe;Averette, Anna F.;Lee, Soo Chan;Kim, Taeyup;Bahn, Yong-Sun;Tripodi, Farida;Ammar, Ron;Doehl, Katja;Niewola-Staszkowska, Karolina;Schmitt, Lutz;Loewith, Robbie J.;Roth, Frederick P.;Sanglard, Dominique;Andes, David;Nislow, Corey;Coccetti, Paola;Gingras, Anne-Claude;Heitman, Joseph;Gunatilaka, A. A. Leslie;Cowen, Leah E.
迫切需要新的战略来治疗侵袭性真菌感染，这是人类死亡的主要原因。我们建立了两种天然产物白藜芦素的活性，它增强了最广泛部署的抗真菌类别对主要人类真菌病原体的活性，阻止耐药的出现，并在哺乳动物感染模型中使耐药病原体对治疗产生反应。利用白藜芦素耐药突变株的基因组测序，生物素化白藜芦素类似物的亲和纯化，以及生化和遗传分析，表明白藜芦素阻止多药外流并抑制全球调节因子TORC1激酶，从而激活蛋白激酶CK2，抑制分子伴侣Hsp90。多药转运体Pdr5上使白藜芦素外排的替换削弱了抗真菌外排，从而阻碍了对药物组合的耐药性。因此，多药外排和TOR信号的双重靶向为逃避耐药的真菌感染性疾病提供了一种强大、广泛有效的治疗策略。
There is an urgent need for new strategies to treat invasive fungal infections, which are a leading cause of human mortality. We establish two activities of the natural product beauvericin, which potentiates the activity of the most widely deployed class of antifungal against the leading human fungal pathogens, blocks the emergence of drug resistance, and renders resistant pathogens responsive to treatment in mammalian infection models. Harnessing genome sequencing of beauvericin-resistant mutants, affinity purification of a biotinylated beauvericin analog, and biochemical and genetic assays reveals that beauvericin blocks multidrug efflux and inhibits the global regulator TORC1 kinase, thereby activating protein kinase CK2 and inhibiting the molecular chaperone Hsp90. Substitutions in the multidrug transporter Pdr5 that enable beauvericin efflux impair antifungal efflux, thereby impeding resistance to the drug combination. Thus, dual targeting of multidrug efflux and TOR signaling provides a powerful, broadly effective therapeutic strategy for fungal infectious disease that evades resistance.
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影响因子：
14.8
作者：
Anderson TM;Clay MC;Cioffi AG;Diaz KA;Hisao GS;Tuttle MD;Nieuwkoop AJ;Comellas G;Maryum N;Wang S;Uno BE;Wildeman EL;Gonen T;Rienstra CM;Burke MD
通讯作者：
Burke MD
影响因子：
14.8
作者：
Arrowsmith CH;Audia JE;Austin C;Baell J;Bennett J;Blagg J;Bountra C;Brennan PE;Brown PJ;Bunnage ME;Buser-Doepner C;Campbell RM;Carter AJ;Cohen P;Copeland RA;Cravatt B;Dahlin JL;Dhanak D;Edwards AM;Frederiksen M;Frye SV;Gray N;Grimshaw CE;Hepworth D;Howe T;Huber KV;Jin J;Knapp S;Kotz JD;Kruger RG;Lowe D;Mader MM;Marsden B;Mueller-Fahrnow A;Müller S;O'Hagan RC;Overington JP;Owen DR;Rosenberg SH;Roth B;Ross R;Schapira M;Schreiber SL;Shoichet B;Sundström M;Superti-Furga G;Taunton J;Toledo-Sherman L;Walpole C;Walters MA;Willson TM;Workman P;Young RN;Zuercher WJ
通讯作者：
Zuercher WJ
影响因子：
4.5
作者：
Diezmann S;Michaut M;Shapiro RS;Bader GD;Cowen LE
通讯作者：
Cowen LE
影响因子：
4.5
作者：
Hill JA;Ammar R;Torti D;Nislow C;Cowen LE
通讯作者：
Cowen LE
影响因子：
3.6
作者：
Bruno, VM;Mitchell, AP
通讯作者：
Mitchell, AP