Attaching NorA efflux pump inhibitors to methylene blue enhances antimicrobial photodynamic inactivation of Escherichia coli and Acinetobacter baumannii in vitro and in vivo.
Attaching NorA efflux pump inhibitors to methylene blue enhances antimicrobial photodynamic inactivation of Escherichia coli and Acinetobacter baumannii in vitro and in vivo.
复制标题
将 NorA 外排泵抑制剂附着到亚甲蓝上可增强体外和体内大肠杆菌和鲍曼不动杆菌的抗菌光动力灭活作用。
DOI：
10.1016/j.bmcl.2018.02.041
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发表时间：
2018
影响因子：
2.7
通讯作者：
Kelso,MichaelJ
中科院分区：
文献类型：
--
作者：
Rineh,Ardeshir;Bremner,JohnB;Hamblin,MichaelR;Ball,AnthonyR;Tegos,GeorgeP;Kelso,MichaelJ
细菌对抗生素的耐药性是全球范围内的公共卫生问题，这是由于标准抗生素治疗的失败率越来越高。抗菌光动力灭活（aPDI）是一种有前途的非抗生素替代治疗局部细菌感染，使用无毒的光敏剂和无害的可见光产生活性氧并杀死微生物。吩噻嗪鎓光敏剂如亚甲蓝（MB）和甲苯胺蓝O是疏水阳离子，其通过多药物外排泵从细菌细胞中自然排出，这降低了它们的有效性。我们最近报道了一种诺拉外排泵抑制剂-亚甲基蓝（EPI-MB）杂合化合物INF 55-（Ac）en-MB的发现，该杂合化合物在体外和体内均显示出增强的对革兰氏阳性细菌耐甲氧西林金黄色葡萄球菌（MRSA）的光动力灭活作用。在这里，我们报告了令人惊讶的观察结果，即INF 55-（Ac）en-MB和携带诺拉外排泵抑制剂的两种相关杂交体INF 55和INF 271也显示出针对革兰氏阴性细菌大肠杆菌和鲍曼不动杆菌的体外aPDI活性增强（相对于MB），尽管这两种物种都不表达诺拉A泵。在鼠aPDI感染模型中，两种杂交体显示出优于MB的上级作用。这些发现激发了对aPDI与EPI-MB杂交体对抗革兰氏阴性病原体的更广泛探索，并对支持其活性的分子机制进行了更详细的研究。
Resistance of bacteria to antibiotics is a public health concern worldwide due to the increasing failure of standard antibiotic therapies. Antimicrobial photodynamic inactivation (aPDI) is a promising non-antibiotic alternative for treating localized bacterial infections that uses non-toxic photosensitizers and harmless visible light to produce reactive oxygen species and kill microbes. Phenothiazinium photosensitizers like methylene blue (MB) and toluidine blue O are hydrophobic cations that are naturally expelled from bacterial cells by multidrug efflux pumps, which reduces their effectiveness. We recently reported the discovery of a NorA efflux pump inhibitor-methylene blue (EPI-MB) hybrid compound INF55-(Ac)en–MB that shows enhanced photodynamic inactivation of the Gram-positive bacterium methicillin-resistantStaphylococcus aureus(MRSA) relative to MB, bothin vitroandin vivo. Here, we report the surprising observation that INF55-(Ac)en–MB and two related hybrids bearing the NorA efflux pump inhibitors INF55 and INF271 also show enhanced aPDI activityin vitro(relative to MB) against the Gram-negative bacteriaEscherichia coliand Acinetobacter baumannii, despite neither species expressing the NorA pump. Two of the hybrids showed superior effects to MB in murine aPDI infection models. The findings motivate wider exploration of aPDI with EPI-MB hybrids against Gram-negative pathogens and more detailed studies into the molecular mechanisms underpinning their activity.