YM155 Inhibits NleB and SseK Arginine Glycosyltransferase Activity.

Congrui Zhu,Samir El Qaidi,Philip R Hardwidge,Anuradha Roy,Peter Mcdonald

doi:10.3390/pathogens10020253

Congrui Zhu, Samir El Qaidi + Show 3 more

Open Access

https://doi.org/10.3390/pathogens10020253

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Journal: Pathogens	Publication Date: Feb 23, 2021
Citations: 8	License type: CC BY 4.0

Affiliation: Kansas State University, University of Kansas

Abstract

The type III secretion system effector proteins NleB and SseK are glycosyltransferases that glycosylate protein substrates on arginine residues. We conducted high-throughput screening assays on 42,498 compounds to identify NleB/SseK inhibitors. Such small molecules may be useful as mechanistic probes and may have utility in the eventual development of anti-virulence therapies against enteric bacterial pathogens. We observed that YM155 (sepantronium bromide) inhibits the activity of Escherichia coli NleB1, Citrobacter rodentium NleB, and both Salmonella enterica SseK1 and SseK2. YM155 was not toxic to mammalian cells, nor did it show cross-reactivity with the mammalian O-linked N-acetylglucosaminyltransferase (OGT). YM155 reduced Salmonella survival in mouse macrophage-like cells but had no direct impact on bacterial growth rates, suggesting YM155 may have utility as a potential anti-virulence inhibitor.

Highlights

Arginine Glycosyltransferase Activity.Enteric bacterial pathogens are important threats to human health and are major sources of foodborne disease
Enterohemorrhagic E. coli (EHEC) are especially important bacterial pathogens because they cause a type of renal failure for which therapies are limited [1]
We used a previously described high-throughput screening (HTS) assay for NleB1 inhibitors that produces a luminescent signal when UDP-glycosylate host protein substrates with βD-N-acetylglucosamine (GlcNAc) is hydrolyzed by NleB1 to liberate UDP [9]

Summary

Introduction

Enteric bacterial pathogens are important threats to human health and are major sources of foodborne disease. Enterohemorrhagic E. coli (EHEC) are especially important bacterial pathogens because they cause a type of renal failure (hemolytic uremic syndrome; HUS) for which therapies are limited [1]. A related attaching/effacing (A/E) pathogen, enteropathogenic E. coli (EPEC), is an important cause of infantile diarrhea. Recent EHEC outbreaks (e.g., O104:H4) have involved a combination of virulence traits characteristic of EHEC and of enteroaggregative E. coli (EAEC; [2]). Salmonella is a leading cause of foodborne illnesses [3]. Understanding how these bacteria evade the mammalian immune system and develop small molecules to subvert these bacterial strategies is an important area of investigation

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