A novel silver-ruthenium-based antimicrobial kills Gram-negative bacteria through oxidative stress-induced macromolecular damage.

IF 3.7 2区 生物学 Q2 MICROBIOLOGY
mSphere Pub Date : 2025-06-25 Epub Date: 2025-05-30 DOI:10.1128/msphere.00017-25
Patrick Ofori Tawiah, Luca Finn Gaessler, Greg M Anderson, Emmanuel Parkay Oladokun, Jan-Ulrik Dahl
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引用次数: 0

Abstract

Amplified by the decline in antibiotic discovery, the rise of antibiotic resistance has become a significant global challenge in infectious disease control. Extraintestinal Escherichia coli (ExPEC), known to be the most common instigators of urinary tract infections (UTIs), represents such a global threat. Novel strategies for more efficient treatments are therefore desperately needed. These include silver nanoparticles, which have been used as antimicrobial surface coatings on catheters to eliminate biofilm-forming uropathogens and reduce the risk of nosocomial infections. AGXX is a promising silver-ruthenium coating that presumably kills bacteria through the generation of reactive oxygen species (ROS). However, neither AGXX's mode of action is fully understood, nor have its effects on Gram-negative bacteria or bacterial response and defense mechanisms toward AGXX been studied in detail. Here, we report that the bactericidal effects of AGXX are primarily based on ROS formation, as supplementation of the media with a ROS scavenger completely abolished AGXX-induced killing. We further show that AGXX impairs the integrity of the bacterial cell envelope and causes substantial protein aggregation and DNA damage already at sublethal concentrations. ExPEC strains appear to be more resistant to the proteotoxic effects of AGXX compared to non-pathogenic E. coli, indicating improved defense capabilities of the uropathogen. Global transcriptomic studies of AGXX-stressed ExPEC revealed a strong oxidative stress response, perturbations in metal homeostasis, as well as the activation of heat shock and DNA damage responses. Finally, we present evidence that ExPEC counteracts AGXX damage through the production of the chaperone polyphosphate, protecting cells from protein aggregation.IMPORTANCEThe rise in drug-resistant bacteria, together with the decline in antibiotic development, requires new strategies for infectious disease control. Gram-negative pathogens are particularly challenging to combat due to their outer membrane. This study highlights the effectiveness of the silver-containing antimicrobial AGXX against the Gram-negative bacterium Escherichia coli. AGXX effectively reduces bacterial survival by interfering with the membrane integrity and causing DNA damage and protein aggregation, which is likely a consequence of uncontrolled generation of oxidative stress. Our findings emphasize AGXX's potential as an antimicrobial surface coating and shed light on potential targets to reduce bacterial resistance to AGXX.

一种新型银钌基抗菌剂通过氧化应激诱导的大分子损伤杀死革兰氏阴性细菌。
由于抗生素发现的减少,抗生素耐药性的上升已成为传染病控制方面的重大全球挑战。众所周知,肠外大肠杆菌(ExPEC)是尿路感染(uti)最常见的煽动者,代表着这样一种全球威胁。因此,迫切需要更有效治疗的新策略。其中包括银纳米颗粒,它已被用作导尿管的抗菌表面涂层,以消除形成生物膜的尿路病原体并降低医院感染的风险。AGXX是一种很有前途的银钌涂层,可能通过产生活性氧(ROS)来杀死细菌。然而,AGXX的作用方式尚不完全清楚,其对革兰氏阴性菌的影响以及细菌对AGXX的反应和防御机制也没有详细的研究。在这里,我们报道AGXX的杀菌作用主要基于ROS的形成,因为添加ROS清除剂的培养基完全消除了AGXX诱导的杀死。我们进一步表明,AGXX损害了细菌细胞膜的完整性,并在亚致死浓度下导致大量蛋白质聚集和DNA损伤。与非致病性大肠杆菌相比,exic菌株似乎对AGXX的蛋白质毒性作用更有抵抗力,这表明尿路病原体的防御能力有所提高。agxx胁迫下的expc在全球转录组学研究中显示出强烈的氧化应激反应、金属稳态扰动以及热休克和DNA损伤反应的激活。最后,我们提供的证据表明,ExPEC通过产生伴侣蛋白聚磷酸酯来抵消AGXX损伤,保护细胞免受蛋白质聚集。耐药细菌的增加,以及抗生素开发的下降,需要新的传染病控制策略。革兰氏阴性病原体由于其外膜特别具有挑战性。本研究强调了含银抗菌剂AGXX对革兰氏阴性杆菌大肠杆菌的有效性。AGXX通过干扰膜完整性,导致DNA损伤和蛋白质聚集,有效降低细菌存活率,这可能是氧化应激不受控制产生的结果。我们的研究结果强调了AGXX作为抗菌表面涂层的潜力,并揭示了降低细菌对AGXX耐药性的潜在靶点。
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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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