How Oxygen Availability Affects the Antimicrobial Efficacy of Host Defense Peptides: Lessons Learned from Studying the Copper-Binding Peptides Piscidins 1 and 3
How Oxygen Availability Affects the Antimicrobial Efficacy of Host Defense Peptides: Lessons Learned from Studying the Copper-Binding Peptides Piscidins 1 and 3
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DOI：
10.3390/ijms20215289
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发表时间：
2019-11-01
影响因子：
5.6
通讯作者：
Purcell, Erin B.
中科院分区：
文献类型：
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作者：
Oludiran, Adenrele;Courson, David S.;Purcell, Erin B.
针对艰难梭菌（C. difficile）感染的新治疗方案的开发是一个重要的公共卫生问题，因为致病细菌对多种抗生素具有高度耐药性。抗菌宿主防御肽 (HDP) 能够非常有效地同时调节免疫系统功能，并通过膜破坏和氧化损伤直接杀死细菌。铜结合 HDP piscidin 1 和 piscidin 3 先前已显示出针对多种革兰氏阴性和革兰氏阳性细菌的有效抗菌活性，但从未在厌氧环境中进行过研究。鱼素和金属离子之间的协同作用增加了有氧细菌的杀灭作用。在这里，我们对艰难梭菌进行了生长抑制和时间杀灭测定，结果表明两种 piscidin 通过杀死细菌细胞来抑制艰难梭菌的增殖。显微镜实验表明肽在膜弯曲的部位积聚。我们发现这两种 piscidin 都能有效对抗对其他胁迫具有高度抵抗力的流行性艰难梭菌菌株。值得注意的是，铜不会增强鱼素对艰难梭菌的活性。因此，虽然鱼素肽的抗菌活性在有氧和厌氧环境中得以保留，但肽-铜相互作用依赖于环境氧气来实现其最大效力。利用HDP（例如piscidin）开发药物需要考虑目标组织中的氧气水平。
The development of new therapeutic options against Clostridioides difficile (C. difficile) infection is a critical public health concern, as the causative bacterium is highly resistant to multiple classes of antibiotics. Antimicrobial host-defense peptides (HDPs) are highly effective at simultaneously modulating the immune system function and directly killing bacteria through membrane disruption and oxidative damage. The copper-binding HDPs piscidin 1 and piscidin 3 have previously shown potent antimicrobial activity against a number of Gram-negative and Gram-positive bacterial species but have never been investigated in an anaerobic environment. Synergy between piscidins and metal ions increases bacterial killing aerobically. Here, we performed growth inhibition and time-kill assays against C. difficile showing that both piscidins suppress proliferation of C. difficile by killing bacterial cells. Microscopy experiments show that the peptides accumulate at sites of membrane curvature. We find that both piscidins are effective against epidemic C. difficile strains that are highly resistant to other stresses. Notably, copper does not enhance piscidin activity against C. difficile. Thus, while antimicrobial activity of piscidin peptides is conserved in aerobic and anaerobic settings, the peptide-copper interaction depends on environmental oxygen to achieve its maximum potency. The development of pharmaceuticals from HDPs such as piscidin will necessitate consideration of oxygen levels in the targeted tissue.