T3SS x Bacterial toxin

Last update 23 Jan 2025

Basic Info

Related Targets

T3SSBacterial toxin

Drugs associated with T3SS x Bacterial toxin

INP-341

Target

Bacterial toxin x T3SS

Mechanism

Bacterial toxin inhibitors [+1]

Active Org.

Université Catholique de Louvain

Originator Org.

Creative Antibiotics AB

Active Indication

Pseudomonas aeruginosa infection

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with T3SS x Bacterial toxin

100 Translational Medicine associated with T3SS x Bacterial toxin

0 Patents (Medical) associated with T3SS x Bacterial toxin

Literatures (Medical) associated with T3SS x Bacterial toxin

02 Sep 2024·PNAS Nexus

In situ deposition of nanobodies by an engineered commensal microbe promotes survival in a mouse model of enterohemorrhagic E. coli

Article

Author: Leong, John M ; Lesser, Cammie F ; Brown, Markus A ; Osburne, Marcia S ; Srivastava, Rajkamal ; Lynch, Jason P ; González-Prieto, Coral ; Lemos, Luisa ; Muscolo, Michele E ; Lin, Catherine Y ; Shrestha, Anishma

AbstractEngineered smart microbes that deliver therapeutic payloads are emerging as treatment modalities, particularly for diseases with links to the gastrointestinal tract. Enterohemorrhagic Escherichia coli (EHEC) is a causative agent of potentially lethal hemolytic uremic syndrome. Given concerns that antibiotic treatment increases EHEC production of Shiga toxin (Stx), which is responsible for systemic disease, novel remedies are needed. EHEC encodes a type III secretion system (T3SS) that injects Tir into enterocytes. Tir inserts into the host cell membrane, exposing an extracellular domain that subsequently binds intimin, one of its outer membrane proteins, triggering the formation of attaching and effacing (A/E) lesions that promote EHEC mucosal colonization. Citrobacter rodentium (Cr), a natural A/E mouse pathogen, similarly requires Tir and intimin for its pathogenesis. Mice infected with Cr(ΦStx2dact), a variant lysogenized with an EHEC-derived phage that produces Stx2dact, develop intestinal A/E lesions and toxin-dependent disease. Stx2a is more closely associated with human disease. By developing an efficient approach to seamlessly modify the C. rodentium genome, we generated Cr_Tir-MEHEC(ΦStx2a), a variant that expresses Stx2a and the EHEC extracellular Tir domain. We found that mouse precolonization with HS-PROT3EcT-TD4, a human commensal E. coli strain (E. coli HS) engineered to efficiently secrete an anti-EHEC Tir nanobody, delayed bacterial colonization and improved survival after challenge with Cr_Tir-MEHEC(ΦStx2a). This study suggests that commensal E. coli engineered to deliver payloads that block essential virulence determinants can be developed as a new means to prevent and potentially treat infections including those due to antibiotic resistant microbes.

30 Jul 2024·mSphere

The yad and yeh fimbrial loci influence gene expression and virulence in enterohemorrhagic Escherichia coli O157:H7

Article

Author: Mortensen, Lindsay ; Sauder, Amber B. ; Willsey, Graham G. ; Gonyar, Laura A. ; Kendall, Melissa M.

ABSTRACT Fimbriae are essential virulence factors for many bacterial pathogens. Fimbriae are extracellular structures that attach bacteria to surfaces. Thus, fimbriae mediate a critical step required for any pathogen to establish infection by anchoring a bacterium to host tissue. The human pathogen enterohemorrhagic Escherichia coli (EHEC) O157:H7encodes 16 fimbriae that may be important for EHEC to initiate infection and allow for productive expression of virulence traits important in later stages of infection, including a type III secretion system (T3SS) and Shiga toxin; however, the roles of most EHEC fimbriae are largely uncharacterized. Here, we provide evidence that two EHEC fimbriae, Yad and Yeh, modulate expression of diverse genes including genes encoding T3SS and Shiga toxin and that these fimbriae are required for robust colonization of the gastrointestinal tract. These findings reveal a significant and previously unappreciated role for fimbriae in bacterial pathogenesis as important determinants of virulence gene expression. IMPORTANCE Fimbriae are extracellular proteinaceous structures whose defining role is to anchor bacteria to surfaces. This is a fundamental step for bacterial pathogens to establish infection in a host. Here, we show that the contributions of fimbriae to pathogenesis are more complex. Specifically, we demonstrate that fimbriae influence expression of virulence traits essential for disease progression in the intestinal pathogen enterohemorrhagic Escherichia coli . Gram-positive and Gram-negative bacteria express multiple fimbriae; therefore, these findings may have broad implications for understanding how pathogens use fimbriae, beyond adhesion, to initiate infection and coordinate gene expression, which ultimately results in disease.

12 Dec 2023·Microbiology Spectrum

L-glutamine protects against enterohemorrhagic Escherichia coli infection by inhibiting bacterial virulence and enhancing host defense concurrently

Article

Author: Kumar, Arvind ; Xue, Yunxin ; Xu, Xuefang ; Zhong, Ying ; Ma, Cong ; Han, Jinping ; Wang, Dai ; Tao, Qian ; Liu, Weijia ; Fang, Dingli ; Lu, Rong ; Li, Yunhe ; Fang, Fang

ABSTRACT Enterohemorrhagic Escherichia coli (EHEC) can colonize the gastrointestinal tract and cause bloody diarrhea in children. Previous studies showed that its pathogenesis could be mediated by metabolites from both the host and microbiota. L-Glutamine (Gln) was found to be depleted in intestinal tissues as the main energy source according to previous studies. Hence, we aimed to determine the effects of Gln on EHEC infection and its underlying mode of action. In this study, a Gln-limited signal was found to activate the type 3 secretion system (T3SS), which is crucial for EHEC infection via perturbation of central metabolism. By shifting the phosphorylation of NtrC, a key regulator in bacterial nitrogen metabolism, Gln stimulates ler transcripts in a σ S -PchA-dependent manner. Our in vivo experiments further demonstrated that Gln supplementation can reduce EHEC colonization in the gastrointestinal tract by repressing T3SS. Moreover, Gln could further attenuate bacterial infection by boosting host defense, which might be dependent on multiple pathways. Besides, our experiments demonstrated that Gln did not induce Shiga-like toxin (Stx) production or cause impairment of gut flora. In conclusion, our study presented evidence that Gln could act against EHEC infection by reducing bacterial virulence and strengthening host defense. Therefore, Gln serves as a promising therapeutic agent for EHEC infection. IMPORTANCE The type 3 secretion system (T3SS) was obtained in many Gram-negative bacterial pathogens, and it is crucial for their pathogenesis. Environmental signals were found to be involved in the expression regulation of T3SS, which was vital for successful bacterial infection in the host. Here, we discovered that L-glutamine (Gln), the most abundant amino acid in the human body, could repress enterohemorrhagic Escherichia coli (EHEC) T3SS expression via nitrogen metabolism and therefore had potential as an antivirulence agent. Our in vitro and in vivo evidence demonstrated that Gln could decline EHEC infection by attenuating bacterial virulence and enhancing host defense simultaneously. We repurpose Gln as a potential treatment for EHEC infection accordingly.

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