C4-Alkoxy-HPD: A Potent Class of Synthetic Modulators Surpassing Nature in AI-2 Quorum Sensing

Tsuchikama, Kyoji; Zhu, Jie; Lowery, Colin A.; Kaufmann, Gunnar F.; Janda, Kim D.

doi:10.1021/ja305532y

Cited by 29 publications

(47 citation statements)

References 30 publications

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“…6.3 ), which activate the AI-2 pathway more potently than DPD, exhibiting submicromolar EC 50 values in a V. harveyi reporter strain (Tsuchikama et al 2012 ). Several C1-substituted DPD analogues act as antagonists of AI-2-based QS, with propyl-DPD 19 and butyl-DPD 20 exhibiting IC 50 values ten- fold below that of DPD (Lowery et al 2008 ).…”

Section: Autoinducer-2 (Ai-2)mentioning

confidence: 99%

Innovative Strategies for Combating Biofilm-Based Infections

Melander

2014

Advances in Experimental Medicine and Biology

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Section: Autoinducer-2 (Ai-2)mentioning

confidence: 99%

Innovative Strategies for Combating Biofilm-Based Infections

Melander

2014

Advances in Experimental Medicine and Biology

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“…Synergistic agonist activity (that is, the analogs did not have any agonist activity on their own but potentiated the activity of AI-2) was found in V. harveyi MM32 whereas antagonist activity was found, especially for propyl- 133 and butyl-DPD 134 , with IC 50 of around 5 μM in the presence of 50 μM AI-2 in S. typhimurium . The same group has also made carbocyclic AI-2 analogs 138 and 139 (Figure 19a) as well as replacing the hydroxyl group at C4 of AI-2 with alkoxy groups 140 – 144 (Figure 19b) [63,64]. The carbocyclic analogs did not display significant QS quenching activities in S. typhimurium or V. harveyi , whereas the C4 alkoxy analogs of DPD showed potent agonist activity in V. harveyi (see Figure 19b).…”

Section: Small Molecule Inhibitors Of Ai-2 Signalingmentioning

confidence: 99%

Small Molecule Inhibitors of AI-2 Signaling in Bacteria: State-of-the-Art and Future Perspectives for Anti-Quorum Sensing Agents

Guo

Gamby

Zheng

et al. 2013

IJMS

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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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“…16 Recently, we reported a purification procedure for the Salmonella LsrK from an E. coli expression system. 22 The purified protein is monomeric and highly active, which rendered it suitable for mechanistic and inhibition studies. Thus, to overcome the limited knowledge of LsrK-DPD and provide a foundation for the design of potent phosphorylation modulators, we herein present a continuous assay, which has allowed a detailed mechanistic pattern to emerge on the interaction between DPD and related congeners with LsrK.…”

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confidence: 99%

Mechanistic Insights into the LsrK Kinase Required for Autoinducer-2 Quorum Sensing Activation

et al. 2013

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In enteric bacteria, the kinase LsrK catalyzes the phosphorylation of the C5-hydroxyl group in the linear form of 4,5-dihydroxy-2,3-pentanedione (DPD), the precursor of the type II bacterial quorum sensing molecule (AI-2). This phosphorylation is required for AI-2 sequestration in the cytoplasm and subsequent derepression of AI-2 related genes necessary for quorum development. While LsrK is a critical enzyme within the DPD quorum sensing relay system, kinetic details of this kinase have yet to be reported. A continuous UV-vis spectrophotometric assay was developed, which allowed steady-state kinetic analysis of LsrK to be undertaken with the substrates ATP and DPD. The data was most consistent with a rapid equilibrium ordered mechanism with ATP binding first: kcat (7.4 ± 0.6 s−1), Km,ATP (150 ± 30 µM) and Km(app),DPD (1.0 ± 0.2 mM). The assay also allowed a DPD substrate profile to be conducted, which provided an unexpected biochemical disconnect between the previous agonist/antagonist cell based reporter assay and the LsrK assay presented herein. Together these findings raise the importance of LsrK and lay the foundation not only for further understanding of this enzyme and its critical biological role but also the rational design of regulatory molecules targeting AI-2 quorum sensing in pathogenic bacteria.

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C4-Alkoxy-HPD: A Potent Class of Synthetic Modulators Surpassing Nature in AI-2 Quorum Sensing

Cited by 29 publications

References 30 publications

Innovative Strategies for Combating Biofilm-Based Infections

Innovative Strategies for Combating Biofilm-Based Infections

Small Molecule Inhibitors of AI-2 Signaling in Bacteria: State-of-the-Art and Future Perspectives for Anti-Quorum Sensing Agents

Mechanistic Insights into the LsrK Kinase Required for Autoinducer-2 Quorum Sensing Activation

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