The antibacterial activity and therapeutic potential of the amphibian-derived peptide TB_KKG6K.

IF 3.7 2区 生物学 Q2 MICROBIOLOGY
mSphere Pub Date : 2025-06-25 Epub Date: 2025-05-19 DOI:10.1128/msphere.01016-24
Cristina Schöpf, Magdalena Knapp, Jakob Scheler, Débora C Coraça-Huber, Alessandra Romanelli, Peter Ladurner, Anna C Seybold, Ulrike Binder, Reinhard Würzner, Florentine Marx
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Abstract

Antimicrobial peptides (AMPs) have great potential to be developed as topical treatments for microbial infections of the skin, including those caused by the gram-positive human pathogen Staphylococcus aureus. Among the AMPs, temporin B (TB) is of particular interest. This 13-amino-acid-long cationic peptide is secreted by the granular glands of the European frog Rana temporaria and represents a primary line of defense against invading pathogens. The objective of this study was to investigate the antibacterial efficacy and the mode of action of the synthetic TB analog, TB_KKG6K, in a drug-resistant clinical isolate of S. aureus and assess the peptide's tolerance and curative potential in an in vitro infection model using three-dimensional human epidermis equivalents (HEEs). The results revealed a high bactericidal efficacy of TB_KKG6K at low micromolar concentrations. The peptide perturbed the bacterial cell membrane integrity by permeabilization and depolarization. TB_KKG6K showed no toxicity in the invertebrate mini-host model Galleria mellonella and a high level of tolerance when topically applied in HEEs. Importantly, the therapeutic potential of TB_KKG6K was confirmed in HEEs infected with S. aureus. The topical application of TB_KKG6K significantly reduced the bacterial load and lowered the pro-inflammatory response in the infected HEEs. These findings reinforce the antibacterial potential and therapeutic efficacy of TB_KKG6K against S. aureus infection, particularly in the context of a cutaneous infection.IMPORTANCEThe emergence of multidrug-resistant bacteria has rendered the exploration of novel therapeutic treatment strategies a pivotal area of research. Among the most promising candidates are amphibian-derived antimicrobial peptides (AMPs), which are ideal for the development of novel drugs due to their multifaceted mode of action. Extensive studies have been conducted on these peptides over the last decade, resulting in the development of temporin B (TB) peptide analogs that have undergone modifications to their primary sequence. These modified analogs have demonstrated enhanced antibacterial and antifungal efficacy, while exhibiting reduced hemolytic activity. TB_KKG6K has the potential to be a promising candidate for topical treatments due to its small size and high antimicrobial activity against pathogens of the human skin. In particular, it demonstrated efficacy against Staphylococcus aureus, a skin commensal that can become an opportunistic pathogen, causing a range of infections from minor skin infections to life-threatening diseases such as bacteremia and sepsis.

两栖动物衍生肽TB_KKG6K的抗菌活性和治疗潜力。
抗菌肽(AMPs)在皮肤微生物感染的局部治疗方面具有很大的潜力,包括革兰氏阳性人类病原体金黄色葡萄球菌引起的皮肤微生物感染。在抗菌肽中,时间B (TB)是特别有趣的。这种长13个氨基酸的阳离子肽是由欧洲蛙临时蛙的颗粒腺体分泌的,是抵御入侵病原体的主要防线。本研究的目的是研究合成结核类似物TB_KKG6K在金黄色葡萄球菌耐药临床分离物中的抗菌效果和作用方式,并利用三维人表皮等效物(HEEs)在体外感染模型中评估该肽的耐受性和治疗潜力。结果表明,TB_KKG6K在低微摩尔浓度下具有较高的杀菌效果。肽通过渗透和去极化干扰细菌细胞膜的完整性。TB_KKG6K对无脊椎动物迷你宿主模型mellongaleria无毒性,局部应用于HEEs时具有较高的耐受性。重要的是,TB_KKG6K在金黄色葡萄球菌感染的HEEs中的治疗潜力得到了证实。局部应用TB_KKG6K可显著降低感染HEEs的细菌负荷,降低促炎反应。这些发现加强了TB_KKG6K对金黄色葡萄球菌感染的抗菌潜力和治疗效果,特别是在皮肤感染的情况下。多重耐药细菌的出现使得探索新的治疗策略成为一个关键的研究领域。其中最有希望的候选者是两栖动物衍生的抗菌肽(AMPs),由于其多方面的作用模式,它是开发新药的理想选择。在过去的十年中,对这些肽进行了广泛的研究,导致了对其初级序列进行修改的temporin B (TB)肽类似物的开发。这些修饰的类似物已显示出增强的抗菌和抗真菌功效,同时表现出降低溶血活性。TB_KKG6K由于其体积小,对人体皮肤病原体具有较高的抗菌活性,有潜力成为局部治疗的有希望的候选物。特别是,它对金黄色葡萄球菌(一种皮肤共生菌,可成为机会性病原体,引起一系列感染,从轻微的皮肤感染到危及生命的疾病,如菌血症和败血症)显示出疗效。
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来源期刊
mSphere
mSphere Immunology and Microbiology-Microbiology
CiteScore
8.50
自引率
2.10%
发文量
192
审稿时长
11 weeks
期刊介绍: mSphere™ is a multi-disciplinary open-access journal that will focus on rapid publication of fundamental contributions to our understanding of microbiology. Its scope will reflect the immense range of fields within the microbial sciences, creating new opportunities for researchers to share findings that are transforming our understanding of human health and disease, ecosystems, neuroscience, agriculture, energy production, climate change, evolution, biogeochemical cycling, and food and drug production. Submissions will be encouraged of all high-quality work that makes fundamental contributions to our understanding of microbiology. mSphere™ will provide streamlined decisions, while carrying on ASM''s tradition for rigorous peer review.
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