Modular Synthetic Routes to Fluorine-Containing Halogenated Phenazine and Acridine Agents That Induce Rapid Iron Starvation in Methicillin-Resistant Staphylococcus aureus Biofilms.
Modular Synthetic Routes to Fluorine-Containing Halogenated Phenazine and Acridine Agents That Induce Rapid Iron Starvation in Methicillin-Resistant Staphylococcus aureus Biofilms.
复制标题
含氟卤代吩嗪和吖啶试剂的模块化合成路线，可诱导耐甲氧西林金黄色葡萄球菌生物膜快速缺铁。
DOI：
10.1021/acsinfecdis.1c00402
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发表时间：
2022-02-11
影响因子：
5.3
通讯作者：
Huigens, Robert W. I. I. I. I. I. I.
中科院分区：
文献类型：
--
作者：
Liu, Ke;Brivio, Massimiliano;Xiao, Tao;Norwood, Verrill M.;Kim, Young S.;Jin, Shouguang;Papagni, Antonio;Vaghi, Luca;Huigens, Robert W. I. I. I. I. I. I.
关键词：
在感染过程中，细菌使用一系列耐药机制来否定抗生素治疗。此外，病原菌形成表面附着的生物膜，其具有代谢休眠的持留细胞的富集群体。细菌对抗生素的侵害会产生耐药性;然而，非复制生物膜天生对所有类别的抗生素都有耐受性。因此，能够根除耐药性和耐药性细菌的分子是重要的。在这里，我们报告模块化的合成路线，含氟卤代吩嗪（HP）和卤代吖啶（HA）剂具有强大的抗菌和生物膜杀死活动。通过包括（1）将氟化苯胺氧化成偶氮苯中间体，（2）与2-甲氧基苯胺的SNAr，和（3）在用三氟乙酸处理后环化成吩嗪的合成策略，快速获得九种氟化吩嗪。利用SNAr和Buchwald-Hartwig方法合成了5个结构相关的吖啶杂环化合物。从这个集中的收集，吩嗪5g，5 h，5i，和吖啶9 c表现出对革兰氏阳性病原体的有效抗菌活性（MIC = 0.04-0.78 μM）。此外，5g和9 c以优异的效力根除金黄色葡萄球菌、表皮葡萄球菌和粪肠球菌生物膜（5g，MBEC = 4.69-6.25 μM; 9 c，MBEC = 4.69-50 μM）。利用实时定量聚合酶链反应（RT-qPCR），5g、5 h、5i和9 c可快速诱导耐甲氧西林链球菌铁摄取标志物isdB和sbnC的转录。金黄色葡萄球菌（MRSA）生物膜，我们得出结论，这些代理商通过铁饥饿。总的来说，氟化吩嗪和吖啶药物可能会在治疗具有挑战性的细菌感染方面取得突破性进展。
During infection, bacteria use an arsenal of resistance mechanisms to negate antibiotic therapies. In addition, pathogenic bacteria form surface-attached biofilms bearing enriched populations of metabolically dormant persister cells. Bacteria develop resistance in response to antibiotic insults; however, nonreplicating biofilms are innately tolerant to all classes of antibiotics. As such, molecules that can eradicate antibiotic-resistant and antibiotic-tolerant bacteria are of importance. Here, we report modular synthetic routes to fluorine-containing halogenated phenazine (HP) and halogenated acridine (HA) agents with potent antibacterial and biofilm-killing activities. Nine fluorinated phenazines were rapidly accessed through a synthetic strategy involving (1) oxidation of fluorinated anilines to azobenzene intermediates, (2) SNAr with 2-methoxyaniline, and (3) cyclization to phenazines upon treatment with trifluoroacetic acid. Five structurally related acridine heterocycles were synthesized using SNAr and Buchwald–Hartwig approaches. From this focused collection, phenazines 5g, 5h, 5i, and acridine 9c demonstrated potent antibacterial activities against Gram-positive pathogens (MIC = 0.04–0.78 μM). Additionally, 5g and 9c eradicated Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis biofilms with excellent potency (5g, MBEC = 4.69–6.25 μM; 9c, MBEC = 4.69–50 μM). Using real-time quantitative polymerase chain reaction (RT-qPCR), 5g, 5h, 5i, and 9c rapidly induce the transcription of iron uptake biomarkers isdB and sbnC in methicillin-resistant S. aureus (MRSA) biofilms, and we conclude that these agents operate through iron starvation. Overall, fluorinated phenazine and acridine agents could lead to ground-breaking advances in the treatment of challenging bacterial infections.
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