In:
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 65, No. 12 ( 2021-11-17)
Abstract:
Infections with enteropathogenic Escherichia coli (EPEC) cause severe diarrhea in children. The noninvasive bacteria adhere to enterocytes of the small intestine and use a type III secretion system (T3SS) to inject effector proteins into host cells to modify and exploit cellular processes in favor of bacterial survival and replication. Several studies have shown that the T3SSs of bacterial pathogens are essential for virulence. Furthermore, the loss of T3SS-mediated effector translocation results in increased immune recognition and clearance of the bacteria. The T3SS is, therefore, considered a promising target for antivirulence strategies and novel therapeutics development. Here, we report the results of a high-throughput screening assay based on the translocation of the EPEC effector protein Tir (translocated intimin receptor). Using this assay, we screened more than 13,000 small molecular compounds of six different compound libraries and identified three substances which showed a significant dose-dependent effect on translocation without adverse effects on bacterial or eukaryotic cell viability. In addition, these substances reduced bacterial binding to host cells, effector-dependent cell detachment, and abolished attaching and effacing lesion formation without affecting the expression of components of the T3SS or associated effector proteins. Moreover, no effects of the inhibitors on bacterial motility or Shiga-toxin expression were observed. In summary, we have identified three new compounds that strongly inhibit T3SS-mediated translocation of effectors into mammalian cells, which could be valuable as lead substances for treating EPEC and enterohemorrhagic E. coli infections.
Type of Medium:
Online Resource
ISSN:
0066-4804
,
1098-6596
DOI:
10.1128/AAC.00958-21
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2021
detail.hit.zdb_id:
1496156-8
detail.hit.zdb_id:
217602-6
SSG:
12
SSG:
15,3
