Host-defense piscidin peptides as antibiotic adjuvants against Clostridioides difficile.
Host-defense piscidin peptides as antibiotic adjuvants against Clostridioides difficile.
复制标题
DOI：
10.1371/journal.pone.0295627
复制
发表时间：
2024
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
孢子形成肠道病原体艰难梭菌导致多重耐药感染，治疗后复发率高。Piscidins 1（p1）和3（p3）是两种对C. difficile，敏化C.在亚致死浓度下测试的临床相关抗生素很难。两种肽均使用氨基末端铜和镍结合基序与Cu 2+结合。在这里，我们研究了两种肽在载脂蛋白和全息状态作为抗生素佐剂对流行株的C。很难我们发现，肽的存在导致甲硝唑，万古霉素和非达霉素的剂量较低，杀死C。很难当与p3结合时，靶向DNA的甲硝唑的活性增强了32倍，p3先前显示出结合和凝聚DNA。相反，万古霉素的活性，其作用于细菌细胞壁，当与膜活性p1-Cu 2+结合时增强64倍。通过显微镜观察，发现C.艰难梭菌细胞和它们的膜的囊泡模拟物中，P1和P3在APO和HOLO状态下的佐剂作用与其中肽能够使抗生素更大地穿透细胞膜以增加它们的生物利用度的作用机制一致。用不同形式的肽获得的效果的变化揭示，虽然所有的鱼杀菌素通常使C.由于肽和抗生素的作用机制难以与抗生素相比，因此可以根据肽和抗生素的潜在作用机制来优化共治疗。总的来说，这项研究强调了抗菌肽作为抗生素佐剂的潜力，以增加目前批准的抗生素剂量的致死率，降低不完全治疗和随之而来的耐药性的风险。
The spore-forming intestinal pathogen Clostridioides difficile causes multidrug resistant infection with a high rate of recurrence after treatment. Piscidins 1 (p1) and 3 (p3), cationic host defense peptides with micromolar cytotoxicity against C. difficile, sensitize C. difficile to clinically relevant antibiotics tested at sublethal concentrations. Both peptides bind to Cu2+ using an amino terminal copper and nickel binding motif. Here, we investigate the two peptides in the apo and holo states as antibiotic adjuvants against an epidemic strain of C. difficile. We find that the presence of the peptides leads to lower doses of metronidazole, vancomycin, and fidaxomicin to kill C. difficile. The activity of metronidazole, which targets DNA, is enhanced by a factor of 32 when combined with p3, previously shown to bind and condense DNA. Conversely, the activity of vancomycin, which acts at bacterial cell walls, is enhanced 64-fold when combined with membrane-active p1-Cu2+. As shown through microscopy monitoring the permeabilization of membranes of C. difficile cells and vesicle mimics of their membranes, the adjuvant effect of p1 and p3 in the apo and holo states is consistent with a mechanism of action where the peptides enable greater antibiotic penetration through the cell membrane to increase their bioavailability. The variations in effects obtained with the different forms of the peptides reveal that while all piscidins generally sensitize C. difficile to antibiotics, co-treatments can be optimized in accordance with the underlying mechanism of action of the peptides and antibiotics. Overall, this study highlights the potential of antimicrobial peptides as antibiotic adjuvants to increase the lethality of currently approved antibiotic dosages, reducing the risk of incomplete treatments and ensuing drug resistance.
登录
查看更多内容
影响因子：
4.9
作者：
Deshpande, Aditi;Wu, Xiaoqian;Hurdle, Julian G.
通讯作者：
Hurdle, Julian G.
DOI：
10.1126/science.aad3292
发表时间：
2016-01-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baym M;Stone LK;Kishony R
通讯作者：
Kishony R
影响因子：
--
作者：
Duong L;Gross SP;Siryaporn A
通讯作者：
Siryaporn A
影响因子：
2.4
作者：
Feuerstadt, Paul;Stong, Laura;Nelson, Winnie W.
通讯作者：
Nelson, Winnie W.
DOI：
10.1073/pnas.0306859101
发表时间：
2004-05-18
影响因子：
11.1
作者：
Cowan, AE;Olivastro, EM;Setlow, P
通讯作者：
Setlow, P