Department of Chemistry, Indian Institute of Technology (IIT) Bombay, Mumbai, Maharashtra 400076, India.
Department of Chemistry, Indian Institute of Technology (IIT) Bombay, Mumbai, Maharashtra 400076, India; IITB-Monash Research Academy, Indian Institute of Technology Bombay, Mumbai, Maharashtra 400076, India.
Biochim Biophys Acta Biomembr. 2019 Jun 1;1861(6):1213-1227. doi: 10.1016/j.bbamem.2019.04.004. Epub 2019 Apr 17.
Lipid structure critically dictates the molecular interactions of drugs with membranes influencing passive diffusion, drug partitioning and accumulation, thereby underpinning a lipid-composition specific interplay. Spurring selective passive drug diffusion and uptake through membranes is an obvious solution to combat growing antibiotic resistance with minimized toxicities. However, the spectrum of complex mycobacterial lipids and lack thereof of suitable membrane platforms limits the understanding of mechanisms underlying drug-membrane interactions in tuberculosis. Herein, we developed membrane scaffolds specific to mycobacterial outer membrane and demonstrate them as improvised research platforms for investigating anti-tubercular drug interactions. Combined spectroscopy and microscopy results reveal an enhanced partitioning of model drug Rifabutin in trehalose dimycolate-containing mycobacterial membrane systems. These effects are apportioned to specific changes in membrane structure, order and fluidity leading to enhanced drug interaction. These findings on the membrane biophysical consequences of drug interactions will offer valuable insights for guiding the design of more effective antibiotic drugs coupled with tuned toxicity profiles.
脂质结构对药物与膜的分子相互作用具有关键影响，影响被动扩散、药物分配和积累，从而支撑了特定的脂质成分相互作用。刺激药物通过膜选择性地被动扩散和摄取，是对抗日益增长的抗生素耐药性并最大程度降低毒性的明显解决方案。然而，复杂的分枝杆菌脂质种类繁多，而合适的膜平台却缺乏，这限制了我们对结核病中药物与膜相互作用机制的理解。在此，我们开发了针对分枝杆菌外膜的膜支架，并将其展示为研究抗结核药物相互作用的临时研究平台。光谱和显微镜结合结果表明，模型药物利福平在含有海藻糖二分枝酸酯的分枝杆菌膜系统中的分配增加。这些影响归因于膜结构、有序性和流动性的特定变化，从而导致药物相互作用增强。这些关于药物相互作用对膜生物物理后果的发现，将为指导更有效的抗生素药物设计提供有价值的见解，同时还可以调整毒性特征。
