Deoxyfluoro-<scp>d</scp>-trehalose (FDTre) analogues as potential PET probes for imaging mycobacterial infection

Rundell, Sarah; Wagar, Zachary L.; Meints, Lisa M.; Olson, Claire D.; O'Neill, Mara K.; Piligian, Brent F.; Poston, Anne W.; Hood, Robin J.; Woodruff, Peter J.; Swarts, Benjamin M.

doi:10.1039/c6ob01734g

Cited by 58 publications

(83 citation statements)

References 61 publications

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“…[20] Our group recently demonstrated that [ 19 F]fluorine-modified trehalose (FDTre) analogues can accumulate in the cytoplasm of M. smegmatis via LpqY-SugABC-mediated uptake, which motivates the investigation of [ 18 F]-FDTre radiotracers as M. tuberculosis -selective positron emission tomography (PET) imaging probes. [29] As shown in the present work, it is conceivable that LpqY-SugABC could be similarly exploited to deliver antimicrobial or anti-biofilm cargo to mycobacteria.…”

Section: Resultsmentioning

confidence: 84%

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

Wolber

Urbanek

Meints

et al. 2017

Carbohydrate Research

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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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Section: Resultsmentioning

confidence: 84%

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

Wolber

Urbanek

Meints

et al. 2017

Carbohydrate Research

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“…In addition, 6‐azido trehalose labeling, deployed in conjunction with click chemistry, was used to confirm the function of MmpL3 as the essential TMM flippase and to characterize antitubercular compounds that inhibit it . Fluorine‐modified trehalose analogues can also be metabolized by mycobacteria, a finding which may pave the way for imaging mycobacterial infections in vivo using positron emission tomography (PET) . Recently, a trehalose analogue bearing a solvatochromic moiety was used as a fluorogenic probe for the rapid detection of Mtb in patient sputum samples .…”

Section: Introductionmentioning

confidence: 99%

Engineering the Mycomembrane of Live Mycobacteria with an Expanded Set of Trehalose Monomycolate Analogues

et al. 2019

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Mycobacteria and related organisms in the Corynebacterineae suborder are characterized by a distinctive outer membrane referred to as the mycomembrane. Biosynthesis of the mycomembrane occurs through an essential process called mycoloylation, which involves antigen 85 (Ag85)‐catalyzed transfer of mycolic acids from the mycoloyl donor trehalose monomycolate (TMM) to acceptor carbohydrates and, in some organisms, proteins. We recently described an alkyne‐modified TMM analogue (O‐AlkTMM‐C7) which, in conjunction with click chemistry, acted as a chemical reporter for mycoloylation in intact cells and allowed metabolic labeling of mycoloylated components of the mycomembrane. Here, we describe the synthesis and evaluation of a toolbox of TMM‐based reporters bearing alkyne, azide, trans‐cyclooctene, and fluorescent tags. These compounds gave further insight into the substrate tolerance of mycoloyltransferases (e.g., Ag85s) in a cellular context and they provide significantly expanded experimental versatility by allowing one‐ or two‐step cell labeling, live cell labeling, and rapid cell labeling via tetrazine ligation. Such capabilities will facilitate research on mycomembrane composition, biosynthesis, and dynamics. Moreover, because TMM is exclusively metabolized by Corynebacterineae, the described probes may be valuable for the specific detection and cell‐surface engineering of Mycobacterium tuberculosis and related pathogens. We also performed experiments to establish the dependence of probe incorporation on mycoloyltransferase activity, results from which suggested that cellular labeling is a function not only of metabolic incorporation (and likely removal) pathway(s), but also accessibility across the envelope. Thus, whole‐cell labeling experiments with TMM reporters should be carefully designed and interpreted when envelope permeability may be compromised. On the other hand, this property of TMM reporters can potentially be exploited as a convenient way to probe changes in envelope integrity and permeability, facilitating drug development studies.

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“…Thus, this work established a robust method for the rapid and convenient synthesis of fluorine-modified trehalose analogues, confirmed that the analogues mimic the structure of native trehalose, and demonstrated that they could bind to mycobacteria through a non-mammalian trehalose recycling pathway. Together, the pioneering work of the Barry and Davis groups, 52,115 combined with our contributions, 82,83 should help to pave the way for continued development of trehalose-based PET imaging probes for tuberculosis diagnostics and other applications.…”

Section: Applications Of Trehalose Analoguesmentioning

confidence: 94%

“…In 2016, we reported the use of TreT catalysis to quantitatively convert non-radioactive 19 F-2-FDG ( 6 ) into 19 F-2-FDTre ( 9 ) in a single step in only 15 minutes (Figure 12). 83 The purification steps took 45 minutes, resulting in the production of a concentrated aqueous solution of pure 19 F-2-FDTre in a total of 60 minutes. This timeframe is compatible with the short half-life of 18 F, so the method should be adaptable to the synthesis of 18 F-2-FDTre.…”

Section: Applications Of Trehalose Analoguesmentioning

confidence: 99%

Tailoring trehalose for biomedical and biotechnological applications

O'Neill

Piligian

Olson

et al. 2017

Pure and Applied Chemistry

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Trehalose is a non-reducing sugar whose ability to stabilize biomolecules has brought about its widespread use in biological preservation applications. Trehalose is also an essential metabolite in a number of pathogens, most significantly the global pathogen Mycobacterium tuberculosis, though it is absent in humans and other mammals. Recently, there has been a surge of interest in modifying the structure of trehalose to generate analogues that have applications in biomedical research and biotechnology. Non-degradable trehalose analogues could have a number of advantages as bioprotectants and food additives. Trehalose-based imaging probes and inhibitors are already useful as research tools and may have future value in the diagnosis and treatment of tuberculosis, among other uses. Underlying the advancements made in these areas are novel synthetic methods that facilitate access to and evaluation of trehalose analogues. In this review, we focus on both aspects of the development of this class of molecules. First, we consider the chemical and chemoenzymatic methods that have been used to prepare trehalose analogues and discuss their prospects for synthesis on commercially relevant scales. Second, we describe ongoing efforts to develop and deploy detectable trehalose analogues, trehalose-based inhibitors, and non-digestible trehalose analogues. The current and potential future uses of these compounds are discussed, with an emphasis on their roles in understanding and combatting mycobacterial infection.

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Deoxyfluoro-d-trehalose (FDTre) analogues as potential PET probes for imaging mycobacterial infection

Cited by 58 publications

References 61 publications

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

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

Engineering the Mycomembrane of Live Mycobacteria with an Expanded Set of Trehalose Monomycolate Analogues

Tailoring trehalose for biomedical and biotechnological applications

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