Polyphosphate-containing bisubstrate analogues as inhibitors of a bacterial cell wall thymidylyltransferase

Smithen, Deborah A.; Forget, Stephanie M.; McCormick, Nicole E.; Syvitski, Raymond T.; Jakeman, David L.

doi:10.1039/c4ob02583k

Cited by 7 publications

(8 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MurA has been a popular target for the design of novel antibiotics, and several inhibitors of MurA have been identified that are active against various bacterial species (87,(142)(143)(144)(145)(146)(147). The chokepoint enzyme glucose-1-phosphate thymidylyltransferase (rfbA/rmlA), involved in O antigen biosynthesis, is also a target in Streptococcus pneumoniae (148) and Pseudomonas aeruginosa (149).…”

Section: Discussionmentioning

confidence: 99%

In silicoidentification of metabolic enzyme drug targets inBurkholderia pseudomallei

Challacombe

2015

Preprint

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

In silicoidentification of metabolic enzyme drug targets inBurkholderia pseudomallei

Challacombe

2015

Preprint

View full text Add to dashboard Cite

show abstract

“…The substrates of G1PTMT are glucose-1-phosphate and deoxy-thymidine triphosphate. Smithen et al (2015) demonstrate that bisubstrate analogs, i.e., a molecule that resembles both substrates in a transient state, are potent inhibitors of G1PTMT of Streptococcus pneumoniae. In P. aeruginosa , Alphey et al (2013) show small thymidine-containing molecules that inhibit G1PTMT through binding the allosteric site.…”

Section: Discussionmentioning

confidence: 94%

A Systematic Strategy to Find Potential Therapeutic Targets for Pseudomonas aeruginosa Using Integrated Computational Models

Filho

Nascimento

Costa

et al. 2021

Front. Mol. Biosci.

View full text Add to dashboard Cite

Pseudomonas aeruginosa is an opportunistic human pathogen that has been a constant global health problem due to its ability to cause infection at different body sites and its resistance to a broad spectrum of clinically available antibiotics. The World Health Organization classified multidrug-resistant Pseudomonas aeruginosa among the top-ranked organisms that require urgent research and development of effective therapeutic options. Several approaches have been taken to achieve these goals, but they all depend on discovering potential drug targets. The large amount of data obtained from sequencing technologies has been used to create computational models of organisms, which provide a powerful tool for better understanding their biological behavior. In the present work, we applied a method to integrate transcriptome data with genome-scale metabolic networks of Pseudomonas aeruginosa. We submitted both metabolic and integrated models to dynamic simulations and compared their performance with published in vitro growth curves. In addition, we used these models to identify potential therapeutic targets and compared the results to analyze the assumption that computational models enriched with biological measurements can provide more selective and (or) specific predictions. Our results demonstrate that dynamic simulations from integrated models result in more accurate growth curves and flux distribution more coherent with biological observations. Moreover, identifying drug targets from integrated models is more selective as the predicted genes were a subset of those found in the metabolic models. Our analysis resulted in the identification of 26 non-host homologous targets. Among them, we highlighted five top-ranked genes based on lesser conservation with the human microbiome. Overall, some of the genes identified in this work have already been proposed by different approaches and (or) are already investigated as targets to antimicrobial compounds, reinforcing the benefit of using integrated models as a starting point to selecting biologically relevant therapeutic targets.

show abstract

“…[37,44,74] Similarly,t he preparation of asymmetrical disubstituted pyro-and polyphosphate derivatives 13 in satisfactory yields presented significant difficulties until recently. [81] Nevertheless, the increasing interest in such compoundsa ssubstrates, cofactors, and regulators in aw ide variety of important biochemical processes demands as earch for new synthetic strategies and activating reagents. Recently,t he new efficient synthesis of terminallyl abeled fluorescent nucleosidep olyphosphate derivatives by activation of inorganic cyclic trimetaphosphateh as been described.…”

Section: Discussionmentioning

confidence: 99%

ChemInform Abstract: How to Form a Phosphate Anhydride Linkage in Nucleotide Derivatives

Sherstyuk¹,

Абрамова²

2016

ChemInform

View full text Add to dashboard Cite

show abstract

Polyphosphate-containing bisubstrate analogues as inhibitors of a bacterial cell wall thymidylyltransferase

Cited by 7 publications

References 31 publications

In silicoidentification of metabolic enzyme drug targets inBurkholderia pseudomallei

In silicoidentification of metabolic enzyme drug targets inBurkholderia pseudomallei

A Systematic Strategy to Find Potential Therapeutic Targets for Pseudomonas aeruginosa Using Integrated Computational Models

ChemInform Abstract: How to Form a Phosphate Anhydride Linkage in Nucleotide Derivatives

Contact Info

Product

Resources

About