A novel ruthenium-silver based antimicrobial potentiates aminoglycoside activity against Pseudomonas aeruginosa.
A novel ruthenium-silver based antimicrobial potentiates aminoglycoside activity against Pseudomonas aeruginosa.
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DOI：
10.1128/msphere.00190-23
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发表时间：
2023-10-24
期刊：
影响因子：
4.8
通讯作者：
Dahl, Jan-Ulrik
中科院分区：
文献类型：
--
作者：
Donkor, Gracious Yoofi;Anderson, Greg M.;Stadler, Michael;Tawiah, Patrick Ofori;Orellano, Carl D.;Edwards, Kevin A.;Dahl, Jan-Ulrik
抗生素耐药性的迅速传播加上新型抗生素发现的减少，对传染病控制构成了重大挑战，只有通过投资新型治疗策略才能缓解这一挑战。包括银在内的替代抗菌剂由于其抑制微生物生长的多种机制而重新引起人们的兴趣。 AGXX 就是一个这样的例子，它是一种广谱抗菌剂，可产生高细胞毒性的活性氧 (ROS)，造成广泛的大分子损伤。由于 ROS 产生和抗生素致死率之间存在联系，我们假设 AGXX 可能会增加传统抗生素的活性。使用革兰氏阴性病原体铜绿假单胞菌，我们筛选了 AGXX 对几种抗生素类别可能的协同作用。我们发现，在亚致死浓度下测试的 AGXX 和氨基糖苷类药物的组合导致细菌存活率迅速呈指数下降，并恢复了卡那霉素耐药菌株的敏感性。 ROS 的产生对 AGXX/氨基糖苷治疗的杀菌作用有显着贡献，这取决于氧气的可用性，并且可以通过添加 ROS 清除剂来减少。此外，缺乏 ROS 解毒/修复基因的铜绿假单胞菌菌株更容易受到 AGXX/氨基糖苷类治疗的影响。我们进一步证明，这种协同相互作用与外膜和内膜通透性的显着增加有关，从而导致抗生素流入增加。我们的研究还表明，AGXX/氨基糖苷介导的杀伤作用需要穿过细菌膜的活跃质子动力。总体而言，我们的研究结果提供了对可以抑制以增加传统抗菌药物活性的细胞靶点的了解。耐药细菌的出现加上抗生素开发的衰退凸显了对新替代品的需求。因此，旨在重新利用传统抗生素的新策略引起了人们的极大兴趣。这些干预措施的必要性是显而易见的，尤其是在革兰氏阴性病原体中，因为它们由于其外膜而特别难以治疗。这项研究强调了抗菌剂 AGXX 在增强氨基糖苷类抗铜绿假单胞菌活性方面的有效性。 AGXX 和氨基糖苷类药物的组合不仅能迅速降低细菌存活率，还能显着使氨基糖苷类耐药的铜绿假单胞菌菌株重新变得敏感。与庆大霉素联合使用，AGXX 会诱导内源性氧化应激增加、膜损伤和铁硫簇破坏。这些发现强调了 AGXX 作为抗生素佐剂开发途径的潜力，并揭示了增强氨基糖苷类活性的潜在靶标。
The rapid dissemination of antibiotic resistance combined with the decline in the discovery of novel antibiotics represents a major challenge for infectious disease control that can only be mitigated by investments in novel treatment strategies. Alternative antimicrobials, including silver, have regained interest due to their diverse mechanisms of inhibiting microbial growth. One such example is AGXX, a broad-spectrum antimicrobial that produces highly cytotoxic reactive oxygen species (ROS) to inflict extensive macromolecular damage. Due to the connections identified between ROS production and antibiotic lethality, we hypothesized that AGXX could potentially increase the activity of conventional antibiotics. Using the gram-negative pathogen Pseudomonas aeruginosa, we screened possible synergistic effects of AGXX on several antibiotic classes. We found that the combination of AGXX and aminoglycosides tested at sublethal concentrations led to a rapid exponential decrease in bacterial survival and restored the sensitivity of a kanamycin-resistant strain. ROS production contributes significantly to the bactericidal effects of AGXX/aminoglycoside treatments, which is dependent on oxygen availability and can be reduced by the addition of ROS scavengers. Additionally, P. aeruginosa strains deficient in ROS detoxifying/repair genes were more susceptible to AGXX/aminoglycoside treatment. We further demonstrate that this synergistic interaction was associated with a significant increase in outer and inner membrane permeability, resulting in increased antibiotic influx. Our study also revealed that AGXX/aminoglycoside-mediated killing requires an active proton motive force across the bacterial membrane. Overall, our findings provide an understanding of cellular targets that could be inhibited to increase the activity of conventional antimicrobials. The emergence of drug-resistant bacteria coupled with the decline in antibiotic development highlights the need for novel alternatives. Thus, new strategies aimed at repurposing conventional antibiotics have gained significant interest. The necessity of these interventions is evident especially in gram-negative pathogens as they are particularly difficult to treat due to their outer membrane. This study highlights the effectiveness of the antimicrobial AGXX in potentiating aminoglycoside activities against P. aeruginosa. The combination of AGXX and aminoglycosides not only reduces bacterial survival rapidly but also significantly re-sensitizes aminoglycoside-resistant P. aeruginosa strains. In combination with gentamicin, AGXX induces increased endogenous oxidative stress, membrane damage, and iron-sulfur cluster disruption. These findings emphasize AGXX’s potential as a route of antibiotic adjuvant development and shed light on potential targets to enhance aminoglycoside activity.
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