The Natural Product Elegaphenone Potentiates Antibiotic Effects against <i>Pseudomonas aeruginosa</i>

Zhao, Weining; Cross, Ashley R.; Crowe‐McAuliffe, Caillan; Muñoz, Angela Weigert; Solinski, Amy E.; Krysiak, Joanna; Goldberg, Joanna B.; Wilson, Daniel N.; Medina, Eva; Wuest, William M.; Sieber, Stephan A.

doi:10.1002/anie.201903472

Cited by 15 publications

(12 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the PAL-ABPP strategy identified the human opioid daunorphan associated with antibacterial action ( Wright et al, 2017a ), LptA and LptD subunits in Escherichia coli periplasm ( Vetterli et al, 2018 ). PAL-ABPP has also been applied for the interaction of the transcriptional regulatory protein AlgP in Gram-positive and -negative bacteria ( Zhao et al, 2019 ).…”

Section: Chemical Probe Approachmentioning

confidence: 99%

Currently Available Strategies for Target Identification of Bioactive Natural Products

Peng

Guo

et al. 2021

Front. Chem.

View full text Add to dashboard Cite

In recent years, biologically active natural products have gradually become important agents in the field of drug research and development because of their wide availability and variety. However, the target sites of many natural products are yet to be identified, which is a setback in the pharmaceutical industry and has seriously hindered the translation of research findings of these natural products as viable candidates for new drug exploitation. This review systematically describes the commonly used strategies for target identification via the application of probe and non-probe approaches. The merits and demerits of each method were summarized using recent examples, with the goal of comparing currently available methods and selecting the optimum techniques for identifying the targets of bioactive natural products.

show abstract

Section: Chemical Probe Approachmentioning

confidence: 99%

Currently Available Strategies for Target Identification of Bioactive Natural Products

Peng

Guo

et al. 2021

Front. Chem.

View full text Add to dashboard Cite

show abstract

“…In this regard, an elegant approach has used a benzophenone containing natural product, elegaphenone, as the starting point to obtain an alkynylated probe (Figure 10B). This probe has enabled to uncover intriguing biological interactions with the transcriptional regulator AlgP in P. aeruginosa [60] . Another set of interesting natural products belong to the class of flavonoids, as they are among the most studied bioactive plant polyphenols but with a limited knowledge about their binding targets.…”

Section: Biomedical Applicationsmentioning

confidence: 99%

“…This probe has enabled to uncover intriguing biological interactions with the transcriptional regulator AlgP in P. aeruginosa. [60] Another set of interesting natural products belong to the class of flavonoids, as they are among the most studied bioactive plant polyphenols but with a limited knowledge about their binding targets. Aiming at shedding some light on this aspect, a series of probes to investigate flavonoid-protein specific interactions ( Figure 10C) have been reported.…”

Section: Use Of Probes For Finding the Molecular Target Of Natural Prmentioning

confidence: 99%

Chemistry for the Identification of Therapeutic Targets: Recent Advances and Future Directions

et al. 2021

View full text Add to dashboard Cite

The increasing availability of chemical probes for specific applications in chemical biology and medicinal chemistry is extensively facilitating our knowledge of biological systems. This understanding has fundamental implications in the development of new efficacious therapeutic strategies. Nowadays, successful drug discovery programs consider identification, engagement, and endogenous levels of the intended therapeutic target from the earliest preclinical stages. All these aspects are addressed with the use of chemical probes, compounds that rely on the use of a particular chemical reaction to give an answer to a specific biological question. In this review we will describe the underlying chemistry and the most recent advances experienced in the field together with their most important biomedical applications.

show abstract

“…The consequences of these alterations in AlgP CTD domain length for granule biogenesis, starvation fitness, and pathogenesis remain to be explored. Recently an alkyne derivative of the natural product elegaphenone, which has antibiotic effects against P. aeruginosa, was shown to bind AlgP, suggesting that AlgP is worthy of further exploration as a possible drug target (53). 2).…”

Section: Functional Significance Of Algp In Starvation Fitness and Pathogenesismentioning

confidence: 99%

The Histone H1-like protein AlgP facilitates even spacing of polyphosphate granules in Pseudomonas aeruginosa

Chawla

Klupt

Patsalo

et al. 2021

Preprint

View full text Add to dashboard Cite

Synthesis of polyphosphate (polyP) is an ancient and universal stress and starvation response in bacteria. In many bacteria, polyP chains come together to form granular superstructures within cells. Some species appear to regulate polyP granule subcellular organization. Despite the critical role of polyP in starvation fitness, the composition of these structures, mechanism(s) underpinning their organization, and functional significance of such organization are poorly understood. We previously determined that granules become transiently evenly spaced on the cell’s long axis during nitrogen starvation in the opportunistic human pathogen Pseudomonas aeruginosa>. Here, we developed a granule-enrichment protocol to screen for polyP granule-localizing proteins. We identified AlgP as a protein that associates with polyP granules. We further discovered that AlgP is required for the even spacing of polyP granules. AlgP is a DNA-binding protein with a 154 amino acid C-terminal domain enriched in ‘KPAA’ repeats and variants of this repeat, with an overall sequence composition similar to the C-terminal tail of eukaryotic histone H1. Granule size, number, and spacing are significantly perturbed in the absence of AlgP, or when AlgP is truncated to remove the C-terminus. The ΔalgP and algPΔCTD mutants having fewer, larger granules. We speculate that AlgP may contribute to spacing by tethering polyP granules to the chromosome, thereby inhibiting fusion with neighboring granules. Our discovery that AlgP facilitates granule spacing allows us for the first time to directly uncouple granule biogenesis from even spacing, and will inform future efforts to explore the functional significance of granule organization on fitness during starvation.

show abstract

The Natural Product Elegaphenone Potentiates Antibiotic Effects against Pseudomonas aeruginosa

Abstract: Natural products represent ar ich source of antibiotics that address versatile cellular targets.

Cited by 15 publications

References 28 publications

Currently Available Strategies for Target Identification of Bioactive Natural Products

Currently Available Strategies for Target Identification of Bioactive Natural Products

Chemistry for the Identification of Therapeutic Targets: Recent Advances and Future Directions

The Histone H1-like protein AlgP facilitates even spacing of polyphosphate granules in Pseudomonas aeruginosa

Contact Info

Product

Resources

About