From in vitro to in cellulo: structure–activity relationship of (2-nitrophenyl)methanol derivatives as inhibitors of PqsD in Pseudomonas aeruginosa

Storz, Michael P.; Allegretta, Giuseppe; Kirsch, Benjamin; Empting, Martin; Hartmann, Rolf W.

doi:10.1039/c4ob00707g

Cited by 38 publications

(47 citation statements)

References 32 publications

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“…This might be due to efflux or permeation problems. The phenomenon that even small changes within a molecule can have drastic effects on the activity in P. aeruginosa was also observed in other projects and emphasizes the need for further insights on the requirement for intracellular activity, especially in the case of Gram‐negative pathogens …”

Section: Resultssupporting

confidence: 53%

Flexible Fragment Growing Boosts Potency of Quorum‐Sensing Inhibitors against Pseudomonas aeruginosa Virulence

et al. 2019

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Hit‐to‐lead optimization is a critical phase in drug discovery. Herein, we report on the fragment‐based discovery and optimization of 2‐aminopyridine derivatives as a novel lead‐like structure for the treatment of the dangerous opportunistic pathogen Pseudomonas aeruginosa. We pursue an innovative treatment strategy by interfering with the Pseudomonas quinolone signal (PQS) quorum sensing (QS) system leading to an abolishment of bacterial pathogenicity. Our compounds act on the PQS receptor (PqsR), a key transcription factor controlling the expression of various pathogenicity determinants. In this target‐driven approach, we made use of biophysical screening via surface plasmon resonance (SPR) followed by isothermal titration calorimetry (ITC)‐enabled enthalpic efficiency (EE) evaluation. Hit optimization then involved growth vector identification and exploitation. Astonishingly, the latter was successfully achieved by introducing flexible linkers rather than rigid motifs leading to a boost in activity on the target receptor and anti‐virulence potency.

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Section: Resultssupporting

confidence: 53%

Flexible Fragment Growing Boosts Potency of Quorum‐Sensing Inhibitors against Pseudomonas aeruginosa Virulence

et al. 2019

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“…The benzimidazole 1 and the nitrophenylmethanol 2 ( Figure 2 ) were synthesized as described in literature (Rahme et al, 2012; Storz et al, 2014). d 4 -HHQ was synthesized following the procedure of HHQ using d 5 -aniline (Lu et al, 2012).…”

Section: Methodsmentioning

confidence: 99%

In-depth Profiling of MvfR-Regulated Small Molecules in Pseudomonas aeruginosa after Quorum Sensing Inhibitor Treatment

et al. 2017

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Pseudomonas aeruginosa is a Gram-negative bacterium, which causes opportunistic infections in immuno-compromised individuals. Due to its multiple resistances toward antibiotics, the development of new drugs is required. Interfering with Quorum Sensing (QS), a cell-to-cell communication system, has shown to be highly efficient in reducing P. aeruginosa pathogenicity. One of its QS systems employs Pseudomonas Quinolone Signal (PQS) and 4-hydroxy-2-heptylquinoline (HHQ) as signal molecules. Both activate the transcriptional regulator MvfR (Multiple Virulence Factor Regulator), also called PqsR, driving the production of QS molecules as well as toxins and biofilm formation. The aim of this work was to elucidate the effects of QS inhibitors (QSIs), such as MvfR antagonists and PqsBC inhibitors, on the biosynthesis of the MvfR-regulated small molecules 2′-aminoacetophenone (2-AA), dihydroxyquinoline (DHQ), HHQ, PQS, and 4-hydroxy-2-heptylquinoline-N-oxide (HQNO). The employed synthetic MvfR antagonist fully inhibited pqs small molecule formation showing expected sigmoidal dose-response curves for 2-AA, HQNO, HHQ and PQS. Surprisingly, DHQ levels were enhanced at lower antagonist concentrations followed by a full suppression at higher QSI amounts. This particular bi-phasic profile hinted at the accumulation of a biosynthetic intermediate resulting in the observed overproduction of the shunt product DHQ. Additionally, investigations on PqsBC inhibitors showed a reduction of MvfR natural ligands, while increased 2-AA, DHQ and HQNO levels compared to the untreated cells were detected. Moreover, PqsBC inhibitors did not show any significant effect in PA14 pqsC mutant demonstrating their target selectivity. As 2-AA is important for antibacterial tolerance, the QSIs were evaluated in their capability to attenuate persistence. Indeed, persister cells were reduced along with 2-AA inhibition resulting from MvfR antagonism, but not from PqsBC inhibition. In conclusion, antagonizing MvfR using a dosage capable of fully suppressing this QS system will lead to a favorable therapeutic outcome as DHQ overproduction is avoided and bacterial persistence is reduced.

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“…Consequently, PqsD has become a highly attractive target and a great amount of work pioneered by the Hartmann group has resulted in inhibitor discovery using a combination of in vitro assay, in silico modelling and chemical lead optimization. Examples of successful inhibitors are represented by the scaffolds of various 2-benzamidobenzoic acids [11,25–26], 2-nitrophenyl derivatives [27–29], ureidothiophene-2-carboxylic acids [24,30], and catechol-based compounds [31]. …”

Section: Resultsmentioning

confidence: 99%

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

Prothiwa¹,

Szamosvári²,

Glasmacher³

et al. 2016

Beilstein J. Org. Chem.

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The human pathogen Pseudomonas aeruginosa uses the pqs quorum sensing system to coordinate the production of its broad spectrum of virulence factors to facilitate colonization and infection of its host. Hereby, the enzyme PqsD is a virulence related quorum sensing signal synthase that catalyzes the central step in the biosynthesis of the Pseudomonas quinolone signals HHQ and PQS. We developed a library of cysteine reactive chemical probes with an alkyne handle for fluorescence tagging and report the selective and highly sensitive in vitro labelling of the active site cysteine of this important enzyme. Interestingly, only one type of probe, with a reactive α-chloroacetamide was capable of covalently reacting with the active site. We demonstrated the potential of our probes in a competitive labelling platform where we screened a library of synthetic HHQ and PQS analogues with heteroatom replacements and found several inhibitors of probe binding that may represent promising scaffolds for the development of customized PqsD inhibitors as well as a chemical toolbox to investigate the activity and active site specificity of the enzyme.

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From in vitro to in cellulo: structure–activity relationship of (2-nitrophenyl)methanol derivatives as inhibitors of PqsD in Pseudomonas aeruginosa

Cited by 38 publications

References 32 publications

Flexible Fragment Growing Boosts Potency of Quorum‐Sensing Inhibitors against Pseudomonas aeruginosa Virulence

Flexible Fragment Growing Boosts Potency of Quorum‐Sensing Inhibitors against Pseudomonas aeruginosa Virulence

In-depth Profiling of MvfR-Regulated Small Molecules in Pseudomonas aeruginosa after Quorum Sensing Inhibitor Treatment

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

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