Self-Assembly of Antimicrobial Peptoids Impacts Their Biological Effects on ESKAPE Bacterial Pathogens.
Self-Assembly of Antimicrobial Peptoids Impacts Their Biological Effects on ESKAPE Bacterial Pathogens.
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DOI：
10.1021/acsinfecdis.1c00536
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发表时间：
2022-03-11
影响因子：
5.3
通讯作者：
Barron AE
中科院分区：
文献类型：
--
作者：
Nielsen JE;Alford MA;Yung DBY;Molchanova N;Fortkort JA;Lin JS;Diamond G;Hancock REW;Jenssen H;Pletzer D;Lund R;Barron AE
抗菌肽（AMPs）是预防和治疗由多药耐药ESKAPE病原体引起的感染的有希望的候选药物，这是大多数医院获得性感染的原因。抗菌肽的临床转化受到限制，部分原因是由于全身给药时明显的毒性，以及由于对蛋白水解的易感性而产生的不稳定性。类肽（序列特异性寡聚n -取代甘氨酸）抵抗蛋白水解消化，因此作为AMP模拟物具有价值。只有少量天然amp如LL-37和多粘菌素在溶液中自组装；抗菌肽是否模仿这些特性尚不清楚。在这里，我们研究了八种设计用于自组装的阳离子抗菌肽的类肽模拟物和两种非组装对照物在水介质中的抗菌功效和动态自组装。这些两亲性肽以不同的方式自我组装，这是由小角度x射线散射确定的；有些采用螺旋束，而另一些则形成核壳椭球或蠕虫状胶束。有趣的是，在体外培养基和宿主模拟条件下，以及在体内，许多这些肽类化合物都显示出有希望的抗菌、抗生物膜和抗脓肿活性。虽然自组装与抗菌效果整体相关，但这种相关性并不完善。某些自组装形态似乎更适合抗菌活性。特别是，与形成椭球状或束状组装的类肽相比，具有高比例的长蠕虫样胶束的类肽对ESKAPE病原体的抗菌、抗生物膜和抗脓肿活性降低。这是与临床医学相关的具有抗体内生物膜感染活性的自组装肽类抗菌药物的首次报道。
Antimicrobial peptides (AMPs) are promising pharmaceutical candidates for the prevention and treatment of infections caused by multidrug-resistant ESKAPE pathogens, which are responsible for the majority of hospital-acquired infections. Clinical translation of AMPs has been limited, in part by apparent toxicity on systemic dosing, and by instability arising from susceptibility to proteolysis. Peptoids (sequence-specific oligo-N-substituted glycines) resist proteolytic digestion, and thus are of value as AMP mimics. Only a few natural AMPs such as LL-37 and polymyxin self-assemble in solution; whether antimicrobial peptoids mimic these properties has been unknown. Here we examine the antibacterial efficacy and dynamic self-assembly in aqueous media of eight peptoid mimics of cationic antimicrobial peptides designed to self-assemble, and two non-assembling controls. These amphipathic peptoids self-assembled in different ways, as determined by small angle X-ray scattering; some adopt helical bundles, while others form core-shell ellipsoidal or worm-like micelles. Interestingly, many of these peptoid assemblies show promising antibacterial, anti-biofilm and anti-abscess activity in vitro in both media and host-mimicking conditions, as well as in vivo. While self-assembly correlated overall with antibacterial efficacy, this correlation was imperfect. Certain self-assembled morphologies seem better suited for antibacterial activity. In particular, a peptoid exhibiting a high fraction of long, worm-like micelles showed reduced antibacterial, antibiofilm and anti-abscess activity against ESKAPE pathogens compared with peptoids that form ellipsoidal or bundled assemblies. This is the first report of self-assembling peptoid antibacterials with activity against in vivo biofilm infections relevant to clinical medicine.
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影响因子：
46.2
作者：
Gan BH;Gaynord J;Rowe SM;Deingruber T;Spring DR
通讯作者：
Spring DR
影响因子：
4.6
作者：
Chongsiriwatana NP;Lin JS;Kapoor R;Wetzler M;Rea JAC;Didwania MK;Contag CH;Barron AE
通讯作者：
Barron AE
影响因子：
7.3
作者：
Hughes, Gareth;Webber, Mark A.
通讯作者：
Webber, Mark A.
影响因子：
9.5
作者：
Gong, Haoning;Sani, Marc-Antoine;Lu, Jian Ren
通讯作者：
Lu, Jian Ren
影响因子：
6.4
作者：
Jacobs AC;Thompson MG;Black CC;Kessler JL;Clark LP;McQueary CN;Gancz HY;Corey BW;Moon JK;Si Y;Owen MT;Hallock JD;Kwak YI;Summers A;Li CZ;Rasko DA;Penwell WF;Honnold CL;Wise MC;Waterman PE;Lesho EP;Stewart RL;Actis LA;Palys TJ;Craft DW;Zurawski DV
通讯作者：
Zurawski DV