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Small molecule inhibitors of AI-2 signaling in bacteria: state-of-the-art and future perspectives for anti-quorum sensing agents.

Guo M, Gamby S, Zheng Y, Sintim HO - Int J Mol Sci (2013)

Bottom Line: These molecules, called autoinducers, are classified as intraspecies (i.e., molecules produced and perceived by the same bacterial species) or interspecies (molecules that are produced and sensed between different bacterial species).Additionally, these molecules have the potential to be used in synthetic biology applications whereby these small molecules are used as inputs to switch on and off AI-2 receptors.In this review, we highlight the state-of-the-art in the development of small molecules that perturb AI-2 signaling in bacteria and offer our perspective on the future development and applications of these classes of molecules.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Maryland, Building 091, College Park, MD 20742, USA.

ABSTRACT
Bacteria respond to different small molecules that are produced by other neighboring bacteria. These molecules, called autoinducers, are classified as intraspecies (i.e., molecules produced and perceived by the same bacterial species) or interspecies (molecules that are produced and sensed between different bacterial species). AI-2 has been proposed as an interspecies autoinducer and has been shown to regulate different bacterial physiology as well as affect virulence factor production and biofilm formation in some bacteria, including bacteria of clinical relevance. Several groups have embarked on the development of small molecules that could be used to perturb AI-2 signaling in bacteria, with the ultimate goal that these molecules could be used to inhibit bacterial virulence and biofilm formation. Additionally, these molecules have the potential to be used in synthetic biology applications whereby these small molecules are used as inputs to switch on and off AI-2 receptors. In this review, we highlight the state-of-the-art in the development of small molecules that perturb AI-2 signaling in bacteria and offer our perspective on the future development and applications of these classes of molecules.

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Related in: MedlinePlus

Proposed transition state of MTAN-catalyzed hydrolysis of MTA (top) and potent MTA analogs (bottom) with their inhibition constants (IC50) for S. pneumoniae (Ki) and V. cholera MTAN.
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f8-ijms-14-17694: Proposed transition state of MTAN-catalyzed hydrolysis of MTA (top) and potent MTA analogs (bottom) with their inhibition constants (IC50) for S. pneumoniae (Ki) and V. cholera MTAN.

Mentions: One way to interrupt QS is to inhibit the synthases that produce autoinducers. As shown in Scheme 1, the key enzymes involved in AI-2 biosynthesis are MTAN (5′-methylthioadenosine/S-adenosylhomo-cycteine nucleosidase) and LuxS; hence, the inhibition of any of these enzymes would decrease the amount of AI-2. In 1976, it was demonstrated in an important paper that MTA analogs could inhibit MTAN from E. coli [92]. Following this discovery, Schramm and co-workers demonstrated that transition state analogs of MTA hydrolysis (Figure 8) strongly inhibited MTAN from several bacteria, including S. pneumoniae, E. coli and V. cholerae [93,94]. 5′-S-substituted immucillin-A analogs aim to mimic an early transition state where ribosyl and adenine bond is partially broken while 5′-S-substituted immucillin DADMe analogs mimic a late transition state whereby adenine is fully dissociated (Figure 8). MTA is also a substrate for the human MTA phosphorylase hence it is possible that some MTA analogs could inhibit the human enzyme to cause toxicity. There are however structural differences between the bacterial MTA nucleosidase and the human MTA phosphorylase to allow for selective targeting of the bacterial enzyme [95,96].


Small molecule inhibitors of AI-2 signaling in bacteria: state-of-the-art and future perspectives for anti-quorum sensing agents.

Guo M, Gamby S, Zheng Y, Sintim HO - Int J Mol Sci (2013)

Proposed transition state of MTAN-catalyzed hydrolysis of MTA (top) and potent MTA analogs (bottom) with their inhibition constants (IC50) for S. pneumoniae (Ki) and V. cholera MTAN.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3794749&req=5

f8-ijms-14-17694: Proposed transition state of MTAN-catalyzed hydrolysis of MTA (top) and potent MTA analogs (bottom) with their inhibition constants (IC50) for S. pneumoniae (Ki) and V. cholera MTAN.
Mentions: One way to interrupt QS is to inhibit the synthases that produce autoinducers. As shown in Scheme 1, the key enzymes involved in AI-2 biosynthesis are MTAN (5′-methylthioadenosine/S-adenosylhomo-cycteine nucleosidase) and LuxS; hence, the inhibition of any of these enzymes would decrease the amount of AI-2. In 1976, it was demonstrated in an important paper that MTA analogs could inhibit MTAN from E. coli [92]. Following this discovery, Schramm and co-workers demonstrated that transition state analogs of MTA hydrolysis (Figure 8) strongly inhibited MTAN from several bacteria, including S. pneumoniae, E. coli and V. cholerae [93,94]. 5′-S-substituted immucillin-A analogs aim to mimic an early transition state where ribosyl and adenine bond is partially broken while 5′-S-substituted immucillin DADMe analogs mimic a late transition state whereby adenine is fully dissociated (Figure 8). MTA is also a substrate for the human MTA phosphorylase hence it is possible that some MTA analogs could inhibit the human enzyme to cause toxicity. There are however structural differences between the bacterial MTA nucleosidase and the human MTA phosphorylase to allow for selective targeting of the bacterial enzyme [95,96].

Bottom Line: These molecules, called autoinducers, are classified as intraspecies (i.e., molecules produced and perceived by the same bacterial species) or interspecies (molecules that are produced and sensed between different bacterial species).Additionally, these molecules have the potential to be used in synthetic biology applications whereby these small molecules are used as inputs to switch on and off AI-2 receptors.In this review, we highlight the state-of-the-art in the development of small molecules that perturb AI-2 signaling in bacteria and offer our perspective on the future development and applications of these classes of molecules.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Maryland, Building 091, College Park, MD 20742, USA.

ABSTRACT
Bacteria respond to different small molecules that are produced by other neighboring bacteria. These molecules, called autoinducers, are classified as intraspecies (i.e., molecules produced and perceived by the same bacterial species) or interspecies (molecules that are produced and sensed between different bacterial species). AI-2 has been proposed as an interspecies autoinducer and has been shown to regulate different bacterial physiology as well as affect virulence factor production and biofilm formation in some bacteria, including bacteria of clinical relevance. Several groups have embarked on the development of small molecules that could be used to perturb AI-2 signaling in bacteria, with the ultimate goal that these molecules could be used to inhibit bacterial virulence and biofilm formation. Additionally, these molecules have the potential to be used in synthetic biology applications whereby these small molecules are used as inputs to switch on and off AI-2 receptors. In this review, we highlight the state-of-the-art in the development of small molecules that perturb AI-2 signaling in bacteria and offer our perspective on the future development and applications of these classes of molecules.

Show MeSH
Related in: MedlinePlus