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

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

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)395-408
Number of pages14
JournalACS Bio & Med Chem Au
Issue number4
Publication statusPublished - 17 Aug 2022


  • bacterial lipids
  • biophysics
  • drug discovery
  • infectious diseases
  • membrane-disruptive agents
  • membrane-drug interactions
  • membranes
  • molecular modeling

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