YM155 Inhibits NleB and SseK Arginine Glycosyltransferase Activity

Zhu, Congrui; Qaidi, Samir El; McDonald, Peter R.; Roy, Anuradha; Hardwidge, Philip R.

doi:10.3390/pathogens10020253

Cited by 7 publications

(6 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While the inhibition of NleB/SseK is concentration-dependent, YM155 did not cross-react with the human OGT enzyme, supporting its specificity to NleB/SseK glycosyltransferases. In addition, YM155 did not exhibit toxicity in RAW264.7 cells (Zhu et al, 2021). However, the effect of YM155-mediated inhibition on survivin has not been characterized in the study.…”

Section: Exotoxinsmentioning

confidence: 86%

Opportunities and Challenges of Bacterial Glycosylation for the Development of Novel Antibacterial Strategies

2021

View full text Add to dashboard Cite

Glycosylation is a ubiquitous process that is universally conserved in nature. The various products of glycosylation, such as polysaccharides, glycoproteins, and glycolipids, perform a myriad of intra- and extracellular functions. The multitude of roles performed by these molecules is reflected in the significant diversity of glycan structures and linkages found in eukaryotes and prokaryotes. Importantly, glycosylation is highly relevant for the virulence of many bacterial pathogens. Various surface-associated glycoconjugates have been identified in bacteria that promote infectious behavior and survival in the host through motility, adhesion, molecular mimicry, and immune system manipulation. Interestingly, bacterial glycosylation systems that produce these virulence factors frequently feature rare monosaccharides and unusual glycosylation mechanisms. Owing to their marked difference from human glycosylation, bacterial glycosylation systems constitute promising antibacterial targets. With the rise of antibiotic resistance and depletion of the antibiotic pipeline, novel drug targets are urgently needed. Bacteria-specific glycosylation systems are especially promising for antivirulence therapies that do not eliminate a bacterial population, but rather alleviate its pathogenesis. In this review, we describe a selection of unique glycosylation systems in bacterial pathogens and their role in bacterial homeostasis and infection, with a focus on virulence factors. In addition, recent advances to inhibit the enzymes involved in these glycosylation systems and target the bacterial glycan structures directly will be highlighted. Together, this review provides an overview of the current status and promise for the future of using bacterial glycosylation to develop novel antibacterial strategies.

show abstract

Section: Exotoxinsmentioning

confidence: 86%

Opportunities and Challenges of Bacterial Glycosylation for the Development of Novel Antibacterial Strategies

2021

View full text Add to dashboard Cite

show abstract

“…We previously published the results of HTS assays in which we identified several small molecules (100066N, 102644N, and YM155) capable of inhibiting NleB/SseK enzyme activity in vitro [ 9 , 10 ]. In those previous studies, we also discovered a potential activity for avasimibe in inhibiting EHEC NleB1 activity.…”

Section: Resultsmentioning

confidence: 99%

“…We previously developed a high-throughput screening (HTS) assay to identify NleB/SseK inhibitors [ 9 , 10 ]. Here, we show that avasimibe ( Figure 1 A), an acyl-coenzyme A: cholesterol acyltransferase inhibitor [ 11 ], also inhibits NleB and SseK enzyme activity, leading to reduced pathogen colonization in macrophage and mouse models of Salmonella and Citrobacter rodentium infection, respectively.…”

Section: Introductionmentioning

confidence: 99%

Repurposing Avasimibe to Inhibit Bacterial Glycosyltransferases

et al. 2022

Self Cite

View full text Add to dashboard Cite

We are interested in identifying and characterizing small molecule inhibitors of bacterial virulence factors for their potential use as anti-virulence inhibitors. We identified from high-throughput screening assays a potential activity for avasimibe, a previously characterized acyl-coenzyme A: cholesterol acyltransferase inhibitor, in inhibiting the NleB and SseK arginine glycosyltransferases from Escherichia coli and Salmonella enterica, respectively. Avasimibe inhibited the activity of the Citrobacter rodentium NleB, E. coli NleB1, and S. enterica SseK1 enzymes, without affecting the activity of the human serine/threonine N-acetylglucosamine (O-GlcNAc) transferase. Avasimibe was not toxic to mammalian cells at up to 200 µM and was neither bacteriostatic nor bactericidal at concentrations of up to 125 µM. Doses of 10 µM avasimibe were sufficient to reduce S. enterica abundance in RAW264.7 macrophage-like cells, and intraperitoneal injection of avasimibe significantly reduced C. rodentium survival in mice, regardless of whether the avasimibe was administered pre- or post-infection. We propose that avasimibe or related derivates created using synthetic chemistry may have utility in preventing or treating bacterial infections by inhibiting arginine glycosyltransferases that are important to virulence.

show abstract

“…Glycosyltransferases NleB and SseK are effector proteins of T3SS and can glycosylate arginine residues of protein substrates. Zhu et al [ 116 ] conducted a high-throughput screening of a library of 42,498 molecules to find NleB/SseK inhibitors. The glycosylation assays found that YM155 ( Figure 8 ) inhibits NleB/SseK in a variety of bacteria, including E. coli NleB1, Citrobacter rodentium NleB, and both S. enterica SseK1 and SseK2.…”

Section: Synthesized Inhibitors Of T3sssmentioning

confidence: 99%

Research Progress on Small Molecular Inhibitors of the Type 3 Secretion System

Liu

Wei

et al. 2022

Molecules

View full text Add to dashboard Cite

The overuse of antibiotics has led to severe bacterial drug resistance. Blocking pathogen virulence devices is a highly effective approach to combating bacterial resistance worldwide. Type three secretion systems (T3SSs) are significant virulence factors in Gram-negative pathogens. Inhibition of these systems can effectively weaken infection whilst having no significant effect on bacterial growth. Therefore, T3SS inhibitors may be a powerful weapon against resistance in Gram-negative bacteria, and there has been increasing interest in the research and development of T3SS inhibitors. This review outlines several reported small-molecule inhibitors of the T3SS, covering those of synthetic and natural origin, including their sources, structures, and mechanisms of action.

show abstract

YM155 Inhibits NleB and SseK Arginine Glycosyltransferase Activity

Cited by 7 publications

References 23 publications

Opportunities and Challenges of Bacterial Glycosylation for the Development of Novel Antibacterial Strategies

Opportunities and Challenges of Bacterial Glycosylation for the Development of Novel Antibacterial Strategies

Repurposing Avasimibe to Inhibit Bacterial Glycosyltransferases

Research Progress on Small Molecular Inhibitors of the Type 3 Secretion System

Contact Info

Product

Resources

About