A new class of synthetic retinoid antibiotics effective against bacterial persisters

Kim Wooseong; Zhu Wenpeng; Hendricks Gabriel Lambert; Van Tyne Daria; Steele Andrew D.; Keohane Colleen E.; Fricke Nico; Conery Annie L.; Shen Steven; Pan Wen; Lee Kiho; Rajamuthiah Rajmohan; Fuchs Beth Burgwyn; Vlahovska Petia M.; Wuest William M.; Gilmore Michael S.; Gao Huajian; Ausubel Frederick M.; Mylonakis Eleftherios

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A new class of synthetic retinoid antibiotics effective against bacterial persisters

机译：一类新的合成类视黄醇抗生素，可有效对抗细菌持久性物质

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A challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant 'persister' subpopulations that exhibit high levels of tolerance to antibiotics(1-3) and have a role in chronic or recurrent infections(4,5). As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans-MRSA infection screen(6) to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.

机译：治疗金黄色葡萄球菌感染的一个挑战是耐甲氧西林的金黄色葡萄球菌（MRSA）菌株的高流行以及形成对抗生素具有高水平耐受性的不生长的休眠``亚群''亚群（1-3）并在慢性或复发性感染中起作用（4,5）。由于常规抗生素不能有效治疗由此类细菌引起的感染，因此迫切需要新型抗菌疗法。在这里，我们使用秀丽隐杆线虫-MRSA感染筛选（6）来鉴定两种合成类视黄醇CD437和CD1530，它们通过破坏脂质双层来杀死生长中的MRSA细胞和持久性MRSA细胞。 CD437和CD1530具有较高的杀灭率，与庆大霉素的协同作用以及抗药性选择的可能性低。全原子分子动力学模拟表明，类维生素A渗透和嵌入脂质双层的能力与其杀菌能力有关。发现CD437的类似物保留了抗persister活性并显示出改善的细胞毒性特征。单独或与庆大霉素组合的CD437和该类似物在慢性MRSA感染的小鼠模型中均显示出相当大的功效。随着进一步的开发和优化，合成类维生素A有望成为一类新型的抗菌药物，用于治疗目前难以治愈的革兰氏阳性细菌感染。

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来源
《Nature》 |2018年第7699期|103-107|共5页
作者
Kim Wooseong; Zhu Wenpeng; Hendricks Gabriel Lambert; Van Tyne Daria; Steele Andrew D.; Keohane Colleen E.; Fricke Nico; Conery Annie L.; Shen Steven; Pan Wen; Lee Kiho; Rajamuthiah Rajmohan; Fuchs Beth Burgwyn; Vlahovska Petia M.; Wuest William M.; Gilmore Michael S.; Gao Huajian; Ausubel Frederick M.; Mylonakis Eleftherios;
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作者单位

Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Infect Dis, Providence, RI 02903 USA;

Brown Univ, Sch Engn, Providence, RI 02903 USA;

Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Infect Dis, Providence, RI 02903 USA;

Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA;

Emory Univ, Dept Chem, Atlanta, GA 30322 USA;

Emory Univ, Dept Chem, Atlanta, GA 30322 USA;

Brown Univ, Sch Engn, Providence, RI 02903 USA;

Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA;

Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Infect Dis, Providence, RI 02903 USA;

Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Infect Dis, Providence, RI 02903 USA;

Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Infect Dis, Providence, RI 02903 USA;

Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Infect Dis, Providence, RI 02903 USA;

Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Infect Dis, Providence, RI 02903 USA;

Northwestern Univ, Dept Engn Sci & Appl Math, Evanston, IL 60208 USA;

Emory Univ, Dept Chem, Atlanta, GA 30322 USA;

Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA;

Brown Univ, Sch Engn, Providence, RI 02903 USA;

Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA;

Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Infect Dis, Providence, RI 02903 USA;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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机译：睡觉时被刺伤：合成类黄醇抗生素杀死细菌泄漏细胞
2. A synthetic antibiotic class overcoming bacterial multidrug resistance [J] . Mitcheltree Matthew J., Pisipati Amarnath, Syroegin Egor A., Nature . 2021,第7885期

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3. Studies on the apoptotic activity of natural and synthetic retinoids: Discovery of a new class of synthetic terphenyls that potently support cell growth and inhibit apoptosis in neuronal and HL-60 cells [J] . Simoni D, Giannini G, Roberti M, Journal of Medicinal Chemistry . 2005,第13期

机译：天然和合成类维生素A的细胞凋亡活性的研究：发现一类新的合成三联苯，其有效支持细胞生长并抑制神经元和HL-60细胞的凋亡
4. RAPID AND EFFECTIVE MULTI-CLASS ANALYSIS OF ANTIBIOTICS IN FEEDINGSTUFFS AT CARRYOVER LEVEL BY LC-MS/MS TECHNIQUES [C] . Ilaria Di Marco Pisciottano, Luigi Giannetti, Bruno Neri, International Mass Spectrometry Conference . 2018

机译：通过LC-MS / MS技术在饲料水平饲料中抗生素的快速有效多阶级分析
5. Controlling bacterial persister cells and biofilms by synthetic brominated furanones. [D] . Pan, Jiachuan. 2013

机译：通过合成溴化呋喃酮控制细菌持久性细胞和生物膜。
6. A new class of synthetic retinoid antibiotics effective against bacterial persisters [O] . Wooseong Kim, Wenpeng Zhu, Gabriel Lambert Hendricks, -1

机译：一类新的合成类视黄醇抗生素可有效对抗细菌持久性物质
7. Stabbed while Sleeping: Synthetic Retinoid Antibiotics Kill Bacterial Persister Cells [O] . Maarten Fauvart, Bram Van den Bergh, Jan Michiels 2018

机译：睡觉时被刺伤：合成类黄醇抗生素杀死细菌泄漏细胞

A new class of synthetic retinoid antibiotics effective against bacterial persisters

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