Mutually Exclusive Interactions of Rifabutin with Spatially Distinct Mycobacterial Cell Envelope Membrane Layers Offer Insights into Membrane-Centric Therapy of Infectious Diseases

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

ACS Bio & Med Chem Au Pub Date : 2022-03-24 DOI:10.1021/acsbiomedchemau.2c00010

Anjana P. Menon, Wanqian Dong, Tzong-Hsien Lee, Marie-Isabel Aguilar*, Mojie Duan* and Shobhna Kapoor*,

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引用次数: 3

Abstract

The mycobacterial cell envelope has spatially resolved inner and outer membrane layers with distinct compositions and membrane properties. However, the functional implication and relevance of this organization remain unknown. Using membrane biophysics and molecular simulations, we reveal a varied interaction profile of these layers with antibiotic Rifabutin, underlined by the structural and chemical makeup of the constituent lipids. The mycobacterial inner membrane displayed the highest partitioning of Rifabutin, which was located exclusively in the lipid head group/interfacial region. In contrast, the drug exhibited specific interaction sites in the head group/interfacial and hydrophobic acyl regions within the outer membrane. Altogether, we show that the design of membrane-active agents that selectively disrupt the mycobacterial outer membrane structure can increase drug uptake and enhance intracellular drug concentrations. Exploiting the mycobacterium-specific membrane–drug interaction profiles, chemotypes consisting of outer membrane-disruptive agents and antitubercular drugs can offer new opportunities for combinational tuberculosis (TB) therapy.

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利福布汀与空间上不同的分枝杆菌包膜层的互斥相互作用为以膜为中心的传染病治疗提供了新的见解

分枝杆菌细胞包膜具有空间分离的内外膜层，具有不同的组成和膜性质。然而，该组织的功能含义和相关性仍然未知。利用膜生物物理学和分子模拟，我们揭示了这些层与抗生素利法布汀的各种相互作用，强调了组成脂质的结构和化学组成。分枝杆菌的内膜对利法布汀的分配最高，它完全位于脂质头组/界面区。相比之下，药物在头基团/界面和外膜内的疏水性酰基区域表现出特定的相互作用位点。总之，我们表明，膜活性剂的设计选择性地破坏分枝杆菌外膜结构可以增加药物摄取和提高细胞内药物浓度。利用分枝杆菌特异性膜-药物相互作用谱，由外膜破坏剂和抗结核药物组成的化学型可以为联合结核病(TB)治疗提供新的机会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Bio & Med Chem Au 药物、生物、化学-

CiteScore

4.10

自引率

0.00%

发文量

期刊介绍： ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.