Inhibiting Fungal Echinocandin Resistance by Small-Molecule Disruption of Geranylgeranyltransferase Type I Activity
Inhibiting Fungal Echinocandin Resistance by Small-Molecule Disruption of Geranylgeranyltransferase Type I Activity
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通过小分子破坏香叶基香叶基转移酶 I 型活性抑制真菌棘白菌素抗性
DOI：
10.1128/aac.02046-19
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发表时间：
2019-12
影响因子：
4.9
通讯作者：
Yang Lu
中科院分区：
文献类型：
--
作者：
Qiangqiang Sun;Kang Xiong;Yuncong Yuan;Jing Yu;Lianjuan Yang;Chao Shen;Chang Su;Yang Lu
棘白菌素类药物被推荐作为侵袭性念珠菌病患者的一线治疗药物，其耐药性一直备受关注。然而，由于缺乏真菌特异性药物靶标，阻碍棘白菌素耐药性的治疗努力受到阻碍。摘要棘白菌素类药物被推荐作为治疗侵袭性念珠菌病的一线药物，其耐药性一直是临床研究的热点。然而，由于缺乏真菌特异性药物靶标，阻碍棘白菌素耐药性的治疗努力受到阻碍。在这里，我们表明，删除CDC 43，β亚基的香叶基香叶基转移酶I型（GGT酶I），赋予超敏反应棘白菌素，这使得GGT酶I一个易于处理的目标，在打击棘白菌素耐药性。Rho 1的膜定位对（1，3）-β-d-葡聚糖合酶Fks 1的激活至关重要，在cdc 43突变体中被破坏，导致细胞壁中葡聚糖的量减少，从而加剧了卡泊芬净对细胞壁的应激。在这种认识的指导下，我们发现L-269289对GGT酶I的选择性化学抑制增强了棘白菌素的活性，并使棘白菌素耐药的白色念珠菌在体外和动物模型中对播散性感染的治疗有反应。此外，L-269289和棘白菌素还以协同方式治疗热带念珠菌和近平滑念珠菌。重要的是，CDC 43的缺失在光滑念珠菌中是致命的。L-269289本身具有杀死C的活性。glabrata，并且当与卡泊芬净组合时其杀真菌活性增强。因此，靶向GGT酶I具有解决棘白菌素耐药念珠菌病的临床挑战的治疗潜力。
Echinocandin resistance in Candida is a great concern, as the echinocandin drugs are recommended as first-line therapy for patients with invasive candidiasis. However, therapeutic efforts to thwart echinocandin resistance have been hampered by a lack of fungal specific drug targets. ABSTRACT Echinocandin resistance in Candida is a great concern, as the echinocandin drugs are recommended as first-line therapy for patients with invasive candidiasis. However, therapeutic efforts to thwart echinocandin resistance have been hampered by a lack of fungal specific drug targets. Here, we show that deleting CDC43, the β subunit of geranylgeranyltransferase type I (GGTase I), confers hypersensitivity to echinocandins, which renders GGTase I a tractable target in combatting echinocandin resistance. The membrane localization of Rho1, which is critical for (1,3)-β-d-glucan synthase Fks1 activation, is disrupted in the cdc43 mutant, resulting in decreased amounts of glucans in the cell wall, thereby exacerbating the cell wall stress upon caspofungin addition. Guided by this insight, we found that selective chemical inhibition of GGTase I by L-269289 potentiates echinocandin activity and renders echinocandin-resistant Candida albicans responsive to treatment in vitro and in animal models for disseminated infection. Furthermore, L-269289 and echinocandins also act in a synergistic manner for the treatment of Candida tropicalis and Candida parapsilosis. Importantly, deletion of CDC43 is lethal in Candida glabrata. L-269289 is active on its own to kill C. glabrata, and its fungicidal activity is enhanced when combined with caspofungin. Thus, targeting GGTase I has therapeutic potential to address the clinical challenge of echinocandin-resistant candidiasis.
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DOI：
10.1016/s0021-9258(18)98729-6
发表时间：
1991-08
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
S. Moores;M. Schaber;S. Mosser;E. Rands;M. B. O'Hara;V. Garsky;M. Marshall;D. Pompliano;J. Gibbs
通讯作者：
S. Moores;M. Schaber;S. Mosser;E. Rands;M. B. O'Hara;V. Garsky;M. Marshall;D. Pompliano;J. Gibbs
影响因子：
64.8
作者：
Nishikawa JL;Boeszoermenyi A;Vale-Silva LA;Torelli R;Posteraro B;Sohn YJ;Ji F;Gelev V;Sanglard D;Sanguinetti M;Sadreyev RI;Mukherjee G;Bhyravabhotla J;Buhrlage SJ;Gray NS;Wagner G;Näär AM;Arthanari H
通讯作者：
Arthanari H
影响因子：
--
作者：
Ochocki JD;Distefano MD
通讯作者：
Distefano MD
影响因子：
2.9
作者：
GHOMASHCHI, F;ZHANG, XH;GELB, MH
通讯作者：
GELB, MH
影响因子：
3.3
作者：
Lu, Yang;Su, Chang;Chen, Jiangye
通讯作者：
Chen, Jiangye