Design, Synthesis, and Evaluation of Carbonate-Linked Halogenated Phenazine-Quinone Prodrugs with Improved Water-Solubility and Potent Antibacterial Profiles,ACS Infectious Diseases

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Design, Synthesis, and Evaluation of Carbonate-Linked Halogenated Phenazine-Quinone Prodrugs with Improved Water-Solubility and Potent Antibacterial Profiles
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2023-03-03 , DOI: 10.1021/acsinfecdis.2c00558
Tao Xiao ₁ , Ke Liu ₁ , Qiwen Gao ₁ , Manyun Chen ₁ , Young S Kim ₂ , Shouguang Jin ₂ , Yousong Ding ₁ , Robert W Huigens ₁

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Pathogenic bacteria have devastating impacts on human health as a result of acquired antibiotic resistance and innate tolerance. Every class of our current antibiotic arsenal was initially discovered as growth-inhibiting agents that target actively replicating (individual, free-floating) planktonic bacteria. Bacteria are notorious for utilizing a diversity of resistance mechanisms to overcome the action of conventional antibiotic therapies and forming surface-attached biofilm communities enriched in (non-replicating) persister cells. To address problems associated with pathogenic bacteria, our group is developing halogenated phenazine (HP) molecules that demonstrate potent antibacterial and biofilm-eradicating activities through a unique iron starvation mode of action. In this study, we designed, synthesized, and investigated a focused collection of carbonate-linked HP prodrugs bearing a quinone trigger to target the reductive cytoplasm of bacteria for bioactivation and subsequent HP release. The quinone moiety also contains a polyethylene glycol group, which dramatically enhances the water-solubility properties of the HP-quinone prodrugs reported herein. We found carbonate-linked HP-quinone prodrugs 11, 21–23 to demonstrate good linker stability, rapid release of the active HP warhead following dithiothreitol (reductive) treatment, and potent antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis, and Enterococcus faecalis. In addition, HP-quinone prodrug 21 induced rapid iron starvation in MRSA and S. epidermidis biofilms, illustrating prodrug action within these surface-attached communities. Overall, we are highly encouraged by these findings and believe that HP prodrugs have the potential to address antibiotic resistant and tolerant bacterial infections.

中文翻译：

具有改善的水溶性和有效抗菌特性的碳酸酯连接的卤代吩嗪醌前药的设计、合成和评估

由于获得性抗生素耐药性和先天耐受性，致病细菌对人类健康产生毁灭性影响。我们目前的抗生素库中的每一类最初都是作为生长抑制剂被发现的，其目标是活跃复制的（个体、自由漂浮的）浮游细菌。细菌因利用多种耐药机制来克服传统抗生素疗法的作用并形成富含（非复制）持续细胞的表面附着生物膜群落而臭名昭著。为了解决与病原菌相关的问题，我们的团队正在开发卤化吩嗪 (HP) 分子，该分子通过独特的铁饥饿作用模式表现出有效的抗菌和生物膜根除活性。在这项研究中，我们设计、合成和研究了一系列碳酸酯连接的 HP 前药，这些前药带有醌触发器，可靶向细菌的还原性细胞质，进行生物激活和随后的 HP 释放。醌部分还含有聚乙二醇基团，其显着增强本文报道的HP-醌前药的水溶性。我们发现碳酸酯连接的 HP-醌前药11 , 21–23表现出良好的连接稳定性，二硫苏糖醇（还原）处理后活性 HP 弹头的快速释放，以及对耐甲氧西林金黄色葡萄球菌(MRSA)、甲氧西林-耐药表皮葡萄球菌和粪肠球菌。此外，HP-醌前药21诱导 MRSA 和表皮葡萄球菌生物膜中的快速铁饥饿，说明了这些表面附着群落中的前药作用。总的来说，我们对这些发现感到非常鼓舞，并相信 HP 前药有潜力解决抗生素耐药性和耐受性细菌感染。

更新日期：2023-03-03

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