Pal Suman, Ramu Vadde, Taye Nandaraj, Mogare Devraj G, Yeware Amar M, Sarkar Dhiman, Reddy D Srinivasa, Chattopadhyay Samit, Das Amitava
Organic Chemistry Division, CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 411008, Maharashtra, India.
Chromatin and Disease Biology Lab, National Centre for Cell Science , Ganeshkhind, Pune 411007, India.
Bioconjug Chem. 2016 Sep 21;27(9):2062-70. doi: 10.1021/acs.bioconjchem.6b00324. Epub 2016 Aug 26.
Fluoroquinolones are third-generation broad spectrum bactericidal antibiotics and work against both Gram-positive and Gram-negative bacteria. Levofloxacin (L), a fluoroquinolone, is widely used in anti-infective chemotherapy and treatment of urinary tract infection and pneumonia. The main pathogen for urinary tract infections is Escherichia coli, and Streptococcus pneumoniae is responsible for pneumonia, predominantly a lower respiratory tract infection. Poor permeability of L leads to the use of higher dose of this drug and excess drug in the outer cellular fluid leads to central nervous system (CNS) abnormality. One way to counter this is to improve the lipophilicity of the drug molecule, and accordingly, we have synthesized two new Levofloxacin derivatives, which participated in the spatiotemporal release of drug via disulfide bond cleavage induced by glutathione (GSH). Recent studies with Streptococcus mutants suggest that it is localized in epithelial lining fluid (ELF) of the normal lower respiratory tract and the effective [GSH] in ELF is ∼430 μM. E. coli typically cause urinary tract infections and the concentration of GSH in porcine bladder epithelium is reported as 0.6 mM for a healthy human. Thus, for the present study we have chosen two important bacteria (Gram + ve and Gram - ve), which are operational in regions having high extracellular GSH concentration. Interestingly, this supports our design of new lipophilic Levofloxacin based prodrugs, which released effective drug on reaction with GSH. Higher lipophilicity favored improved uptake of the prodrugs. Site specific release of the drug (L) could be achieved following a glutathione mediated biochemical transformation process through cleavage of a disulfide bond of these purpose-built prodrugs. Further, appropriate design helped us to demonstrate that it is possible also to control the kinetics of the drug release from respective prodrugs. Associated luminescence enhancement helps in probing the release of the drug from the prodrug in bacteria and helps in elucidating the mechanistic pathway of the transformation. Such an example is scarce in the contemporary literature.
氟喹诺酮类是第三代广谱杀菌抗生素，对革兰氏阳性菌和革兰氏阴性菌均有作用。左氧氟沙星（L）作为一种氟喹诺酮类药物，广泛应用于抗感染化疗以及尿路感染和肺炎的治疗。尿路感染的主要病原体是大肠杆菌，肺炎主要由下呼吸道感染引起，其病原体是肺炎链球菌。L的渗透性较差，导致该药物需要使用更高剂量，而细胞外液中药物过量会导致中枢神经系统（CNS）异常。解决这一问题的一种方法是提高药物分子的亲脂性，因此，我们合成了两种新的左氧氟沙星衍生物，它们通过谷胱甘肽（GSH）诱导的二硫键断裂参与药物的时空释放。最近对变异链球菌的研究表明，它存在于正常下呼吸道的上皮衬液（ELF）中，ELF中的有效[GSH]约为430μM。大肠杆菌通常引起尿路感染，据报道，健康人的猪膀胱上皮中GSH的浓度为0.6 mM。因此，在本研究中，我们选择了两种重要的细菌（革兰氏阳性菌和革兰氏阴性菌），它们在细胞外GSH浓度较高的区域起作用。有趣的是，这支持了我们基于亲脂性左氧氟沙星设计前药的方案，该前药与GSH反应时会释放出有效药物。更高的亲脂性有利于前药的吸收改善。通过这些特制前药的二硫键断裂，经谷胱甘肽介导的生化转化过程，可以实现药物（L）的位点特异性释放。此外，合理的设计帮助我们证明，也有可能控制药物从各自前药中释放的动力学。相关的发光增强有助于探测药物从前药在细菌中的释放，并有助于阐明转化的机制途径。这种例子在当代文献中很少见。
ACS Appl Mater Interfaces. 2015-9-29
Ann Pharmacother. 1998-3
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