Immune Targeting of Mycobacteria through Cell Surface Glycan Engineering

Area of Science:

• Microbiology
• Immunology
• Drug Discovery

Background:

• Mycobacterial infections like tuberculosis and leprosy pose significant health challenges.
• The unique cell envelope of Mycobacteria confers intrinsic drug tolerance, complicating treatment and fostering resistance.
• Novel therapeutic strategies are needed to complement existing antibiotic treatments.

Purpose of the Study:

• To develop a novel strategy for targeting mycobacterial cell surfaces to enhance host immune responses.
• To create antibody-recruiting molecules (ARMs) that specifically decorate mycobacterial glycans.
• To investigate the potential of ARMs in augmenting macrophage-mediated bacterial clearance.

Main Methods:

• Synthesized Mycobacterium-specific ARMs (Tre-DNPs) comprising a trehalose targeting moiety and a dinitrophenyl hapten.
• Demonstrated specific incorporation of Tre-DNPs into outer-membrane glycolipids of *Mycobacterium smegmatis* via trehalose metabolism.
• Assessed the enhanced phagocytosis of Tre-DNP-modified *M. smegmatis* by macrophages in the presence of anti-DNP antibodies.

Main Results:

• Tre-DNP ARMs specifically targeted and decorated the cell surface of *Mycobacterium smegmatis*.
• The decorated bacteria successfully recruited anti-DNP antibodies to the cell surface.
• Macrophage phagocytosis of modified mycobacteria was significantly enhanced when anti-DNP antibodies were present, showing proof-of-concept.

Conclusions:

• The developed ARM strategy effectively flags mycobacteria for enhanced immune recognition and clearance.
• The conserved metabolic pathways for ARM incorporation across Mycobacteriales offer broad applicability.
• This approach holds promise for developing new immune-targeting therapies against diverse mycobacterial diseases.