Inhibition of P. aeruginosa c-di-GMP phosphodiesterase RocR and swarming motility by a benzoisothiazolinone derivative

Zheng, Yue; Tsuji, Genichiro; Opoku‐Temeng, Clement; Sintim, Herman O.

doi:10.1039/c6sc02103d

Cited by 40 publications

(31 citation statements)

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“…reported a benzoisothiazolinone derivative ( 37 ) which was found by in silico screening against the structure of an E . coli PDE . This compound inhibited selectively c‐di‐GMP hydrolysis of the locally acting PDE RocR of P. aeruginosa with a K i of 83 μ m , but did not inhibit three other PDEs of P. aeruginosa whereby global cellular c‐di‐GMP levels remained unaffected (Figure ).…”

Section: Interference With Flagellar Motor Assembly and Functionmentioning

confidence: 99%

Inhibitors of Bacterial Swarming Behavior

Rütschlin

Böttcher

2019

Chemistry A European J

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Bacteria can migrate in groups of flagella‐driven cells over semisolid surfaces. This coordinated form of motility is called swarming behavior. Swarming is associated with enhanced virulence and antibiotic resistance of various human pathogens and may be considered as favorable adaptation to the diverse challenges that microbes face in rapidly changing environments. Consequently, the differentiation of motile swarmer cells is tightly regulated and involves multi‐layered signaling networks. Controlling swarming behavior is of major interest for the development of novel anti‐infective strategies. In addition, compounds that block swarming represent important tools for more detailed insights into the molecular mechanisms of the coordination of bacterial population behavior. Over the past decades, there has been major progress in the discovery of small‐molecule modulators and mechanisms that allow selective inhibition of swarming behavior. Herein, an overview of the achievements in the field and future directions and challenges will be presented.

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Section: Interference With Flagellar Motor Assembly and Functionmentioning

confidence: 99%

Inhibitors of Bacterial Swarming Behavior

Rütschlin

Böttcher

2019

Chemistry A European J

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“…Recently several reports have documented the roles of cyclic dinucleotide (c-di-GMP, c-di-AMP and cGAMP) phosphodiesterases in bacterial virulence 1 as well in innate immunity (cleavage of 2 0 3 0 -cGAMP) and probes, 55,56 such as the ones reported in this manuscript could be used to conrm the activity of expressed PDE enzymes or used to screen for inhibitors of dinucleotide phosphodiesterases. 19,57 …”

Section: Resultsmentioning

confidence: 99%

“…2), slightly decreased upon cleavage by RocR, 15 a c-di-GMP PDE that we have been interested in developing inhibitors against. 19 However, MANT-cdi-GMP has a bulky uorophore group appended to 2 0 -position of c-di-GMP and this steric block could account for the poor substrate prole for some PDEs. We recently reported that the replacement of one of the native nucleobases of c-di-GMP with 2-AP afforded a uorescent analog (compound 1, Fig.…”

Section: 42mentioning

confidence: 99%

“…4A). Also, in the presence of a RocR benzoisothiazolinone inhibitor, 19 the change in uorescence intensity was minimal (see Fig. 4A).…”

mentioning

confidence: 99%

“…There is however a paucity of inhibitors that target cyclic dinucleotide signaling [16][17][18][19] and no clinical drug is as yet in development for inhibiting cyclic dinucleotide signaling, but the case is different with signaling by cyclic mononucleotides such as cGMP 20 and cAMP, 21 which were identied in 1960s. For example, Sildenal (Viagra®), a cGMP PDE5 inhibitor, is used to treat erectile dysfunction.…”

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confidence: 99%

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Fluorescent analogs of cyclic and linear dinucleotides as phosphodiesterase and oligoribonuclease activity probes

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Enzymatic Syntheses and Applications of Fluorescent Cyclic Dinucleotides

Ludford

Fin

et al. 2020

Chemistry A European J

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Bacterial cyclic dinucleotides (CDNs) play important roles in regulating biofilm formation, motility and virulence. In eukaryotic cells, theses bacterial CDNs are recognized as pathogen‐associated molecular patterns (PAMPs) and trigger an innate immune response. We report the photophysical analyses of a novel group of enzymatically synthesized emissive CDN analogues comprised of two families of isomorphic ribonucleotides. The highly favorable photophysical features of the CDN analogues, when compared to their non‐emissive natural counterparts, are used to monitor in real time the dinucleotide cyclase‐mediated synthesis and phosphodiesterase (PDE)‐mediated hydrolysis of homodimeric and mixed CDNs, providing effective means to probe the activities of two classes of bacterial enzymes and insight into their biomolecular recognition and catalytic features.

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Inhibition of P. aeruginosa c-di-GMP phosphodiesterase RocR and swarming motility by a benzoisothiazolinone derivative

Abstract: Pseudomonas aeruginosa swarming motility can be inhibited with a small molecule inhibitor of c-di-GMP phosphodiesterase, RocR.

Cited by 40 publications

References 70 publications

Inhibitors of Bacterial Swarming Behavior

Inhibitors of Bacterial Swarming Behavior

Fluorescent analogs of cyclic and linear dinucleotides as phosphodiesterase and oligoribonuclease activity probes

Enzymatic Syntheses and Applications of Fluorescent Cyclic Dinucleotides

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