The trehalose-specific transporter LpqY-SugABC is required for antimicrobial and anti-biofilm activity of trehalose analogues in Mycobacterium smegmatis

• Published in: Carbohydrate research Vol. 450; pp. 60 - 66
• Main Authors: Wolber, Jeffrey M., Urbanek, Bailey L., Meints, Lisa M., Piligian, Brent F., Lopez-Casillas, Irene C., Zochowski, Kailey M., Woodruff, Peter J., Swarts, Benjamin M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 10-10-2017
• Subjects: Anti-Bacterial Agents - pharmacology; ATP-Binding Cassette Transporters - metabolism; Bacterial Proteins - metabolism; Biofilms - drug effects; Dose-Response Relationship, Drug; Mycobacterium smegmatis - drug effects; Mycobacterium smegmatis - metabolism; Mycobacterium smegmatis - physiology; Protein Transport - drug effects; Trehalose - metabolism
• ISSN: 0008-6215; 1873-426X
• DOI: 10.1016/j.carres.2017.08.003

Mycobacteria, including the bacterial pathogen that causes human tuberculosis, possess distinctive pathways for synthesizing and utilizing the non-mammalian disaccharide trehalose. Trehalose metabolism is essential for mycobacterial viability and has been linked to in vitro biofilm formation, which may bear relevance to in vivo drug tolerance. Previous research has shown that some trehalose analogues bearing modifications at the 6-position inhibit growth of various mycobacterial species. In this work, 2-, 5-, and 6-position-modified trehalose analogues were synthesized using our previously reported 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 ABC transporter LpqY-SugABC was essential for 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 acyltransferases or trehalose dimycolate hydrolase. Although the potency of the described compounds in in vitro growth and biofilm assays is moderate, this study reports the first trehalose-based mycobacterial biofilm inhibitors and reinforces the concept of exploiting unique sugar uptake pathways to deliver inhibitors and other chemical cargo to mycobacteria.
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•A panel of trehalose analogues was prepared using a one-step chemoenzymatic synthesis method.•Trehalose analogues were shown to inhibit growth and biofilm formation in Mycobacterium smegmatis.•Several trehalose analogues were shown to be selective inhibitors of biofilm formation.•Trehalose analogue activity was dependent upon cellular uptake via the trehalose-specific transporter LpqY-SugABC.