Targeting the Ag85 Complex in Mycobacteria
Pharmacy
Final Report Abstract
The cell envelope of Mycobacterium tuberculosis (M. tuberculosis) consists of extractable lipids and long-chain mycolic acids, which are covalently linked to peptidoglycan via an arabinogalactan network. The outer membrane contains the essential disaccharide trehalose and the glycolipids trehalose dimycolate (TDM) and trehalose monomycolate (TMM). The extracellular Ag85 protein complex catalyses the reversible transesterification between TMM molecules, enabling the anchoring of trehalose in the membrane as mono- or dimycolate species. Ag85 exhibits broad substrate specificity, accepting modified trehalose derivatives. This substrate promiscuity has been exploited for the development of trehalose-fluorophore conjugates and PET probes for mycobacterial diagnostics. Ag85 is essential for the intracellular survival of M. tuberculosis, and homologous enzymes have been identified in M. smegmatis, M. abscessus, and M. bovis. Since trehalose mycolates are unique to Actinobacteria, Ag85 represents an attractive target for novel antimycobacterial therapeutics. In 2019, our group reported the synthesis of trehalose-photosensitizer conjugates with antimicrobial activity and their Ag85-mediated integration into mycobacterial membranes. Building on this work, we developed trehalose conjugates with cleavable linkers to chemotherapeutic agents, which were successfully incorporated into M. smegmatis and M. bovis BCG. Modified BCG strains exhibited significantly enhanced cytotoxicity against bladder cancer cells compared to the wild-type strain. These findings highlight the potential of trehalose conjugates for targeted mycobacterial functionalization in cancer therapy applications.
Publications
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Poster Abstract “Hochschule trifft Industrie 2024”: Trehalose-drug or photosensitizer conjugates for selective targeting of mycobacteria
Michael Grimmeisen & Claudia Jessen-Trefzer
