In silico Predicted Glucose‐1‐phosphate Uridylyltransferase (GalU) Inhibitors Block a Key Pathway Required for Listeria Virulence

Kuenemann, Mélaine A.; Spears, Patricia A.; Orndorff, Paul E.; Fourches, Denis

doi:10.1002/minf.201800004

Cited by 16 publications

(21 citation statements)

References 37 publications

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“…Molecular docking of the 37 listerial UDPG:PP hit compounds from our previous study (Kuenemann et al, 2018) was performed toward the newly built strains D39/R6 and TIGR4 UDPG:PP homology models, as described in the "Materials and Methods" section. First, the reproducibility of our docking results regarding listerial UDPG:PP using the newest version of 2019 Glide was tested.…”

Section: Resultsmentioning

confidence: 99%

“…As glucose plays a pivotal role in a variety of cell processes, UDPG:PP is found to play a role in the integrity of cell membranes, functionality of flagellae, production of LPS and the pneumococcal polysaccharide capsule (Komeda et al, 1977;Deng et al, 2010). While UDPG:PP has previously been proposed as a valid novel drug target, up until recently no inhibitors were known (Kuenemann et al, 2018). In 2018, UDPG:PP inhibitors against listerial UDPG:PP were screened using an in silico modeling approach, leading to the identification of several compounds with anti-listerial activity.…”

Section: Discussionmentioning

confidence: 99%

“…In L. monocytogenes, UDPG:PP is important in the first step of wall teichoic acid galactosylation, which renders the use of antibiotic cefotaxime useless. Addition of UDPG:PP inhibitors elevated the MIC values of this antibiotic drastically, thereby proving UDPG:PP was effectively inhibited (Kuenemann et al, 2018). In this study, a similar approach to identify pneumococcal UDPG:PP inhibitors was conducted.…”

Section: Discussionmentioning

confidence: 99%

“…As the crystal structure of pneumococcal UDPG:PP is currently unknown, it's exact conformation and location of the binding site is unsure. Therefore, a recently published computational model based on listerial UDPG:PP was optimized for S. pneumoniae (Kuenemann et al, 2018). Adaptation of this model led to the identification of several hit compounds, which were characterized, predicted and selected in silico using 3D molecular docking in order to have a binding affinity that could result in some enzyme inhibitory activity.…”

Section: Introductionmentioning

confidence: 99%

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In vitro and in vivo Evaluation of in silico Predicted Pneumococcal UDPG:PP Inhibitors

et al. 2020

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Pneumonia, of which Streptococcus pneumoniae is the most common causative agent, is considered one of the three top leading causes of death worldwide. As seen in other bacterial species, antimicrobial resistance is on the rise for this pathogen. Therefore, there is a pressing need for novel antimicrobial strategies to combat these infections. Recently, uridine diphosphate glucose pyrophosphorylase (UDPG:PP) has been put forward as a potential drug target worth investigating. Moreover, earlier research demonstrated that streptococci lacking a functional galU gene (encoding for UDPG:PP) were characterized by significantly reduced in vitro and in vivo virulence. Therefore, in this study we evaluated the anti-virulence activity of potential UDPG:PP inhibitors. They were selected in silico using a tailor-made streptococcal homology model, based on earlier listerial research. While the compounds didn't affect bacterial growth, nor affected in vitro adhesion to and phagocytosis in macrophages, the amount of polysaccharide capsule was significantly reduced after co-incubation with these inhibitors. Moreover, co-incubation proved to have a positive effect on survival in an in vivo Galleria mellonella larval infection model. Therefore, rather than targeting bacterial survival directly, these compounds proved to have an effect on streptococcal virulence by lowering the amount of polysaccharide and thereby probably boosting recognition of this pathogen by the innate immune system. While the compounds need adaptation to broaden their activity to more streptococcal strains rather than being strain-specific, this study consolidates UDPG:PP as a potential novel drug target.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vitro and in vivo Evaluation of in silico Predicted Pneumococcal UDPG:PP Inhibitors

et al. 2020

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“…Our previous case studies using 3D docking with homology models of proteins showed that reasonable docking poses can be obtained. [32,33] OvCHT1 sequence was collected from the Universal Protein Resource [34] (Uniprot code Q25615). The homology model was created based upon a single protein template (PDB code 1WAW -CHIT1 chitinase 1) that shared 37% sequence identity with OvCHT1 ( Figure 4A).…”

Section: Homology Modeling and Protein Preparationmentioning

confidence: 99%

Cheminformatics Modeling of Closantel Analogues for Treating River Blindness

Ma¹,

Zin²,

Kuchibhotla³

et al. 2020

Preprint

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Onchocerciasis (also known as river blindness) is a neglected tropical disease caused by the Onchocerca volvulus parasitic nematode. Currently, the only approved drug for treating this disease is ivermectin, which is a broad-spectrum antiparasitic agent. However, signs of resistance towards ivermectin have started to emerge. New therapeutic agents are thus urgently needed. The OvCHT1 chitinase enzyme from O. volvulus has been established as a relevant biological target for combatting river blindness. The veterinary anthelmintic drug closantel has been found to be a potent, micro-molar OvCHT1 inhibitor. Herein, we investigated the chemical space of closantel and all its synthesized analogues, focusing on the analysis of their potential binding modes towards OvCHT1. First, we conducted an unsupervised hierarchical clustering to group highly similar analogues and explore structure-activity relationships. Second, we conducted a structure-based molecular docking to predict and study the binding modes of all 57 closantel analogues in the active site of OvCHT1. Third, we screened more than 4 million lead-like compounds from the ZINC library to identify other structurally similar ligands that could potentially bind to OvCHT1. The cheminformatics analysis of the closantel analogues illustrated how minor structural changes in closantel analogues can impact their OvCHT1 activity.

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Cheminformatics Analysis of Fluoroquinolones and their Inhibition Potency Against Four Pathogens

Borrel

Melander

Fourches

2020

Molecular Informatics

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Drug‐resistant bacteria are a worldwide public health concern. As the prevalence of multi‐drug resistant pathogens outpaces the discovery of new antibacterials, it is of importance to explore the structure‐activity relationships for series of known bactericides with proven scaffolds. Herein, we assembled a set of 507 fluoroquinolone analogues all experimentally tested for their inhibition potency against four pathogens: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. We relied on cheminformatics techniques to characterize and cluster them based on their structural similarity and analyzed the structure‐activity relationships identified for each cluster of fluoroquinolones. Then, we utilized machine learning techniques to develop and validate predictive QSAR models for computing the inhibition potencies (pMIC) of analogues for each pathogen. These QSAR models afforded reasonable external prediction performances (R2≥0.6, MAE∼0.4). This study confirmed that (i) there are both global and local inter‐pathogen concordance regarding the antibacterial potency of fluoroquinolones, (ii) small clusters of fluoroquinolone analogues are characterized by unique patterns of strain selectivity and potency, the latter being potentially useful to design new analogues with enhanced potency and/or selectivity towards a given pathogen, and (iii) robust QSAR models were obtained allowing for future design of new bioactive fluoroquinolones.

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In silico Predicted Glucose‐1‐phosphate Uridylyltransferase (GalU) Inhibitors Block a Key Pathway Required for Listeria Virulence

Cited by 16 publications

References 37 publications

In vitro and in vivo Evaluation of in silico Predicted Pneumococcal UDPG:PP Inhibitors

In vitro and in vivo Evaluation of in silico Predicted Pneumococcal UDPG:PP Inhibitors

Cheminformatics Modeling of Closantel Analogues for Treating River Blindness

Cheminformatics Analysis of Fluoroquinolones and their Inhibition Potency Against Four Pathogens

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