Establishing the selective phospholipid membrane coordination, permeation and lysis properties for a series of 'druggable' supramolecular self-associating antimicrobial amphiphiles.
Establishing the selective phospholipid membrane coordination, permeation and lysis properties for a series of 'druggable' supramolecular self-associating antimicrobial amphiphiles.
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DOI：
10.1039/d2sc02630a
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发表时间：
2022-08-24
期刊：
影响因子：
8.4
通讯作者：
Hiscock, Jennifer R.
中科院分区：
文献类型：
--
作者：
Boles, Jessica E.;Bennett, Charlotte;Baker, Jennifer;Hilton, Kira L. F.;Kotak, Hiral A.;Clark, Ewan R.;Long, Yifan;White, Lisa J.;Lai, Hin Yuk;Hind, Charlotte K.;Sutton, J. Mark;Garrett, Michelle D.;Cheasty, Anne;Ortega-Roldan, Jose L.;Charles, Mark;Haynes, Cally J. E.;Hiscock, Jennifer R.
抗菌素耐药性的上升仍然是人类面临的最大全球健康威胁之一。此外，由于交叉压力的碰撞，新型抗生素的开发几乎已经停止。在此，我们确定了14个结构相关的超分子自缔合两亲物对临床相关的革兰氏阳性耐甲氧西林金黄色葡萄球菌和革兰氏阴性大肠杆菌的抗菌功效。我们建立了这些药物选择性靶向不同组成的磷脂膜的能力，通过结合计算主机：客体复合物形成模拟，合成囊泡裂解，粘附和膜流动性实验，以及我们的新型1H NMR CPMG nanodisc配位测定，以验证这类化合物的潜在作用模式，并能够生产更有效的下一代抗菌剂。最后，我们选择了一个7化合物子集，通过完成各种体内和体外DMPK研究，显示两种先导化合物表现出“可药用”的特征。计算和合成磷脂囊泡/纳米盘测定的组合用于研究一类抗微生物剂的作用模式，而一系列DMPK研究确定了药物的可药性。
The rise of antimicrobial resistance remains one of the greatest global health threats facing humanity. Furthermore, the development of novel antibiotics has all but ground to a halt due to a collision of intersectional pressures. Herein we determine the antimicrobial efficacy for 14 structurally related supramolecular self-associating amphiphiles against clinically relevant Gram-positive methicillin resistant Staphylococcus aureus and Gram-negative Escherichia coli. We establish the ability of these agents to selectively target phospholipid membranes of differing compositions, through a combination of computational host:guest complex formation simulations, synthetic vesicle lysis, adhesion and membrane fluidity experiments, alongside our novel 1H NMR CPMG nanodisc coordination assays, to verify a potential mode of action for this class of compounds and enable the production of evermore effective next-generation antimicrobial agents. Finally, we select a 7-compound subset, showing two lead compounds to exhibit ‘druggable’ profiles through completion of a variety of in vivo and in vitro DMPK studies. A combination of computational and synthetic phospholipid vesicle/nanodisc assays are used to investigate the mode of action for a class of antimicrobial agents, while a range of DMPK studies establish agent druggability.
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影响因子：
3.9
作者：
Boles JE;Ellaby RJ;Shepherd HJ;Hiscock JR
通讯作者：
Hiscock JR
影响因子：
8.4
作者：
Hilton KLF;Manwani C;Boles JE;White LJ;Ozturk S;Garrett MD;Hiscock JR
通讯作者：
Hiscock JR
影响因子：
7.7
作者：
Knight GM;Glover RE;McQuaid CF;Olaru ID;Gallandat K;Leclerc QJ;Fuller NM;Willcocks SJ;Hasan R;van Kleef E;Chandler CI
通讯作者：
Chandler CI
影响因子：
3.9
作者：
Dora NO;Blackburn E;Boles JE;Williams GT;White LJ;Turner SEG;Hothersall JD;Askwith T;Doolan JA;Mulvihill DP;Garrett MD;Hiscock JR
通讯作者：
Hiscock JR
影响因子：
4.6
作者：
Boles, Jessica E.;Williams, George T.;Hiscock, Jennifer R.
通讯作者：
Hiscock, Jennifer R.