Ronco Troels, Jørgensen Nadia S, Holmer Iben, Kromann Sofie, Sheikhsamani Ehsan, Permin Anders, Svenningsen Søren W, Christensen Jørn B, Olsen Rikke H
Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Animal Science, Faculty of Agriculture, Ferdowsi University, Mashhad, Iran.
Front Microbiol. 2020 Sep 30;11:560798. doi: 10.3389/fmicb.2020.560798. eCollection 2020.
The emergence of multidrug-resistant bacteria constitutes a significant public health issue worldwide. Consequently, there is an urgent clinical need for novel treatment solutions. It has been shown that phenothiazines can act as adjuvants to antibiotics whereby the minimum inhibitory concentration (MIC) of the antibiotic is decreased. However, phenothiazines do not perform well , most likely because they can permeate the blood-brain (BBB) barrier and cause severe side-effects to the central nervous system. Therefore, the aim of this study was to synthesize a promazine derivate that would not cross the BBB but retain its properties as antimicrobial helper compound. Surprisingly, studies showed that the novel compound, JBC 1847 exhibited highly increased antimicrobial activity against eight Gram-positive pathogens (MIC, 0.5-2 mg/L), whereas a disc diffusion assay indicated that the properties as an adjuvant were lost. JBC 1847 showed significant ( < 0.0001) activity against a strain compared with the vehicle, in an wound infection model. However, both and analyses showed that JBC 1847 possesses strong affinity for human plasma proteins and an Ames test showed that generally, it is a non-mutagenic compound. Finally, predictions suggested that the compound was not prone to pass the BBB and had a suitable permeability to the skin. In conclusion, JBC 1847 is therefore suggested to hold potential as a novel topical agent for the clinical treatment of skin and soft tissue infections, but pharmacokinetics and pharmacodynamics need to be further investigated.
多重耐药菌的出现是全球范围内一个重大的公共卫生问题。因此，临床上迫切需要新的治疗方案。已表明吩噻嗪可作为抗生素的佐剂，从而降低抗生素的最低抑菌浓度（MIC）。然而，吩噻嗪的效果不佳，很可能是因为它们能够穿透血脑屏障（BBB）并对中枢神经系统造成严重副作用。因此，本研究的目的是合成一种不会穿过血脑屏障但保留其作为抗菌辅助化合物特性的丙嗪衍生物。令人惊讶的是，研究表明新型化合物JBC 1847对八种革兰氏阳性病原体表现出高度增强的抗菌活性（MIC，0.5 - 2 mg/L），而纸片扩散试验表明其作为佐剂的特性丧失。在伤口感染模型中，与赋形剂相比，JBC 1847对某菌株显示出显著（<0.0001）活性。然而，蛋白质印迹法和免疫共沉淀分析均表明JBC 1847对人血浆蛋白具有很强的亲和力，并且艾姆斯试验表明，总体而言，它是一种非致突变化合物。最后，计算机模拟预测表明该化合物不易穿过血脑屏障，并且对皮肤具有合适的渗透性。总之，因此建议JBC 1847有潜力作为一种新型局部用药用于皮肤和软组织感染的临床治疗，但药代动力学和药效学还需要进一步研究。
