Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267.
Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
Proc Natl Acad Sci U S A. 2020 Mar 3;117(9):4921-4930. doi: 10.1073/pnas.1911927117. Epub 2020 Feb 18.
Antibiotic-resistant superbug bacteria represent a global health problem with no imminent solutions. Here we demonstrate that the combination (termed AB569) of acidified nitrite (A-NO) and Na-EDTA (disodium ethylenediaminetetraacetic acid) inhibited all Gram-negative and Gram-positive bacteria tested. AB569 was also efficacious at killing the model organism in biofilms and in a murine chronic lung infection model. AB569 was not toxic to human cell lines at bactericidal concentrations using a basic viability assay. RNA-Seq analyses upon treatment of with AB569 revealed a catastrophic loss of the ability to support core pathways encompassing DNA, RNA, protein, ATP biosynthesis, and iron metabolism. Electrochemical analyses elucidated that AB569 produced more stable SNO proteins, potentially explaining one mechanism of bacterial killing. Our data implicate that AB569 is a safe and effective means to kill pathogenic bacteria, suggesting that simple strategies could be applied with highly advantageous therapeutic/toxicity index ratios to pathogens associated with a myriad of periepithelial infections and related disease scenarios.
具有耐药性的超级细菌是一个全球性的健康问题，目前尚无解决办法。在这里，我们证明酸化亚硝酸盐（A-NO）和 Na-EDTA（乙二胺四乙酸二钠）的组合（称为 AB569）抑制了所有测试的革兰氏阴性和革兰氏阳性细菌。AB569 还能有效地杀死生物膜中的模型生物和小鼠慢性肺部感染模型中的细菌。在使用基本生存能力测定法的杀菌浓度下，AB569 对人细胞系没有毒性。用 AB569 处理 后进行的 RNA-Seq 分析显示，其支持涵盖 DNA、RNA、蛋白质、ATP 生物合成和铁代谢的核心途径的能力灾难性丧失。电化学分析阐明 AB569 产生了更稳定的 SNO 蛋白，这可能解释了一种杀菌机制。我们的数据表明，AB569 是一种安全有效的杀死致病细菌的方法，这表明可以应用简单的策略，以非常有利的治疗/毒性指数比值，针对与多种上皮周围感染和相关疾病情况相关的病原体。
