Mycobacteria, including the bacterial pathogen that causes human tuberculosis, possess a remarkable network of pathways for synthesizing and utilizing the non-mammalian disaccharide trehalose. Trehalose metabolism is essential for mycobacterial viability and was recently linked to the in vitro formation of biofilms, which may bear relevance to in vivo drug tolerance. In this work, 2-, 5-, and 6-position-modified trehalose analogues were synthesized using a one-step chemoenzymatic method and shown to inhibit growth and biofilm formation in the two- to three-digit micromolar range in Mycobacterium smegmatis. The trehalose-specific transporter SugABC-LpqY was essential for both antimicrobial and anti-biofilm activity, suggesting that inhibition by monosubstituted trehalose analogues requires cellular uptake and does not proceed via direct action on extracellular targets such as antigen 85. The anti-biofilm activity of some of the analogues was more pronounced than their antimicrobial activity.

Inhibition of mycobacterial growth and biofilm formation by chemoenzymatically synthesized trehalose analogues

253rd National Meeting (2017)

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