THCz: Small molecules with antimicrobial activity that block cell wall lipid intermediates.
THCz: Small molecules with antimicrobial activity that block cell wall lipid intermediates.
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DOI：
10.1073/pnas.2108244118
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发表时间：
2021-11-23
影响因子：
11.1
通讯作者：
Mellroth P
中科院分区：
文献类型：
--
作者：
Reithuber E;Wixe T;Ludwig KC;Müller A;Uvell H;Grein F;Lindgren AEG;Muschiol S;Nannapaneni P;Eriksson A;Schneider T;Normark S;Henriques-Normark B;Almqvist F;Mellroth P
考虑到对大多数抗生素的抗药性的惊人出现和对新抗生素的需要，在这里发现一种小分子类别THCZ，它对革兰氏阳性菌和选定的革兰氏阴性菌具有杀菌活性，这是最重要的。我们发现THCZ以细胞膜合成为靶点，可以很容易地合成和修饰，而且体外不容易产生耐药性。因此，THCZ是开发细菌细胞壁抑制剂的有前途的支架材料。新出现的抗生素耐药性要求鉴定新的抗菌化合物类别。建立了一种基于肺炎球菌自溶素介导的裂解诱导的细菌全细胞筛选方法，以筛选潜在的细菌细胞壁合成抑制剂。一种含有1-氨基取代四氢咔唑(THCZ)支架的HIT类，含有两个必需的胺基，对低微摩尔范围内的广泛的革兰氏阳性和选定的革兰氏阴性病原体显示出杀菌活性。作用模式研究表明，THCZ通过靶向含有十一碳烯基焦磷酸的脂质中间体抑制细胞膜的合成，从而同时抑制肽聚糖、磷壁酸和多糖胶囊的生物合成。THCZ在体外不易产生耐药性，与天然脂类II结合的抗生素相比，这些小分子的合成和修饰非常容易，这使得THCZ有望成为开发细胞壁靶向抗菌剂的支架。
Considering the alarming emergence of resistance to most antibiotics and the need for new antibiotics, the finding here of a small-molecule class, THCz, that displayed bactericidal activity against gram-positive and selected gram-negative bacteria, is of the greatest importance. We found that THCz target the cell envelope synthesis and can easily be synthesized and modified, and resistance did not readily develop in vitro. Thus, THCz are promising scaffolds for development of bacterial cell wall inhibitors. Emerging antibiotic resistance demands identification of novel antibacterial compound classes. A bacterial whole-cell screen based on pneumococcal autolysin-mediated lysis induction was developed to identify potential bacterial cell wall synthesis inhibitors. A hit class comprising a 1-amino substituted tetrahydrocarbazole (THCz) scaffold, containing two essential amine groups, displayed bactericidal activity against a broad range of gram-positive and selected gram-negative pathogens in the low micromolar range. Mode of action studies revealed that THCz inhibit cell envelope synthesis by targeting undecaprenyl pyrophosphate–containing lipid intermediates and thus simultaneously inhibit peptidoglycan, teichoic acid, and polysaccharide capsule biosynthesis. Resistance did not readily develop in vitro, and the ease of synthesizing and modifying these small molecules, as compared to natural lipid II–binding antibiotics, makes THCz promising scaffolds for development of cell wall–targeting antimicrobials.
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影响因子：
3.1
作者：
Kansal, RG;McGeer, A;Kotb, M
通讯作者：
Kotb, M
影响因子：
3.2
作者：
Cartee, RT;Forsee, WT;Yother, J
通讯作者：
Yother, J
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3.2
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HOLTJE, JV
影响因子：
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作者：
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通讯作者：
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影响因子：
3.7
作者：
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