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A Photoactivatable Free Mycolic Acid Probe to Investigate Mycobacteria-Host Interactions.
Kingsley C Agu1, Nicholas Banahene1,2, Carolina Santamaria3
1Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, Michigan 48859, United States.
ACS Infectious Diseases
|April 14, 2025
Summary
Free mycolic acids (fMA) from Mycobacterium tuberculosis are key to immune evasion. Researchers developed a novel probe to identify fMA-interacting proteins, revealing TREM2 as a key host immune receptor.
Area of Science:
- Microbiology
- Immunology
- Chemical Biology
Background:
- Mycolic acids are essential lipids in the mycobacterial outer membrane.
- Free mycolic acids (fMA) contribute to Mycobacterium tuberculosis biofilm formation and immune evasion.
- Understanding fMA-protein interactions is crucial for deciphering M. tuberculosis pathogenesis.
Purpose of the Study:
- To synthesize a functionalized free mycolic acid (fMA) analogue probe.
- To investigate fMA-protein interactions in host macrophages.
- To identify host factors involved in M. tuberculosis immune evasion.
Main Methods:
- Chemical synthesis of a fMA analogue probe (x-Alk-MA) with photo-cross-linking and clickable functionalities.
- Asymmetric hydrogenation and diastereoselective alkylation for precise stereochemistry.
- Live-cell photolabeling and analysis in macrophage models.
Main Results:
- The synthesized x-Alk-MA probe successfully mimicked native mycolic acid responses.
- Selective photolabeling identified TREM2 as a direct host cell receptor for fMA.
- TREM2 plays a role in suppressing macrophage activation during M. tuberculosis infection.
Conclusions:
- The developed chemical probe and methodology enable the study of fMA-protein interactions.
- Identification of TREM2 highlights its significance in M. tuberculosis immune evasion strategies.
- Further research can elucidate the role of fMA in mycobacterial physiology and host-pathogen dynamics.
