Trehalose Conjugation Enhances Toxicity of Photosensitizers against Mycobacteria

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Abstract
Trehalose is a natural glucose-derived disaccharide found in the cell wall of mycobacteria. It enters the mycobacterial cell through a highly specific trehalose transporter system. Subsequently, trehalose is equipped with mycolic acid species and is incorporated into the cell wall as trehalose monomycolate or dimycolate. Here, we investigate the phototoxicity of several photosensitizer trehalose conjugates and take advantage of the promiscuity of the extracellular Ag85 complex, which catalyzes the attachment of mycolic acids to trehalose and its analogues. We find that processing by Ag85 enriches and tethers photosensitizer trehalose conjugates directly into the mycomembrane. Irradiation of the conjugates triggers singlet oxygen formation, killing mycobacterial cells more efficiently, as compared to photosensitizers without trehalose conjugation. The conjugates are potent antimycobacterial agents that are, per se, affected neither by permeability issues nor by detoxification mechanisms via drug efflux. They could serve as interesting scaffolds for photodynamic therapy of mycobacterial infections.
Funding Information
  • Vedeck? Grantov? Agent?ra M?VVa? SR a SAV (VEGA 1/0301/18)
  • Ministerium f?r Wissenschaft, Forschung und Kunst Baden-W?rttemberg (33-7533.-30-10/25/27)
  • Ministerstvo ?kolstva, vedy, v?skumu a ?portu Slovenskej republiky (0395/2016)
  • Department of Biotechnology , Ministry of Science and Technology (BT/PR8616/MED/29/793/2013, BT/PR19140/MED/29/1104/2016)
  • Chinese Research Council

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