Quaternized 1,2,3-Triazolyl Content and Modulation Potentiate Antibacterial and Antifungal Activities of Amphipathic Peptoids.

IF 4 2区医学 Q2 CHEMISTRY, MEDICINAL

ACS Infectious Diseases Pub Date : 2024-11-08 Epub Date: 2024-10-11 DOI:10.1021/acsinfecdis.4c00591

Cassandra Guerinot, Mélodie Malige, Kathakali De, Marc Maresca, Nicolas Charbonnel, Elise Courvoisier-Dezord, Nicolas Vidal, Olivier Roy, Frederic Laurent, Jérôme Josse, Christopher Aisenbrey, Burkhard Bechinger, Christiane Forestier, Sophie Faure

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引用次数: 0

Abstract

Bioinspired from cationic antimicrobial peptides, sequence-defined triazolium-grafted peptoid oligomers (6- to 12-mer) were designed to adopt an amphipathic helical polyproline I-type structure. Their evaluation on a panel of bacterial strains (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis), pathogenic fungi (Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus), and human cells (hRBC, BEAS-2B, Caco-2, HaCaT, and HepG2) enabled the identification of two heptamers with improved activity to selectively fight Staphylococcus aureus pathogens. Modulation of parameters such as the nature of the triazolium and hydrophobic/lipophilic side chains, the charge content, and the sequence length drastically potentiates activity and selectivity. Besides, the ability to block the proinflammatory effect induced by lipopolysaccharide or lipoteichoic acid was also explored. Finally, biophysical studies by circular dichroism and fluorescence spectroscopies strongly supported that the bactericidal effect of these triazolium-grafted oligomers was primarily due to the selective disruption of the bacterial membrane.

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季铵化 1,2,3-三唑含量和调制可增强两性肽的抗菌和抗真菌活性。

受阳离子抗菌肽的生物启发，我们设计了序列明确的三唑鎓接枝肽类寡聚体（6-12-mer），采用两性螺旋聚脯氨酸 I 型结构。在一组细菌菌株（大肠杆菌、铜绿假单胞菌、金黄色葡萄球菌和粪肠球菌）、致病真菌（白色念珠菌、新生隐球菌和熏曲霉菌）上对它们进行了评估、和烟曲霉）以及人体细胞（hRBC、BEAS-2B、Caco-2、HaCaT 和 HepG2），从而鉴定出两种七聚物，它们具有更强的选择性抗击金黄色葡萄球菌病原体的活性。三唑侧链和疏水/亲油性侧链的性质、电荷含量和序列长度等参数的改变可显著提高活性和选择性。此外，研究人员还探讨了阻断脂多糖或脂太古酸诱导的促炎效应的能力。最后，通过圆二色性和荧光光谱进行的生物物理研究有力地证明了这些三唑接枝低聚物的杀菌作用主要是由于选择性地破坏了细菌膜。

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来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

期刊介绍： ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.