Abstract
SummaryAnti‐virulence (AV) compounds are a promising alternative to traditional antibiotics for fighting bacterial infections. The Type Three Secretion System (T3SS) is a well‐studied and attractive AV target, given that it is widespread in more than 25 species of Gram‐negative bacteria, including enterohemorrhagic E. coli (EHEC), and as it is essential for host colonization by many pathogens. In this work, we designed, synthesized and tested a new series of compounds that block the functionality of the T3SS of EHEC. Affinity chromatography experiments identified the primary target of the compounds as the T3SS needle pore protein EspD, which is essential for effector protein translocation into host cells. These data were supported by mechanistic studies that determined the coiled‐coil domain 1 of EspD as a key compound‐binding site, thereby preventing correct assembly of the T3SS complex on the cell surface. However, binding of inhibitors to EspD or deletion of EspD itself did not result in transcriptional down‐regulation of effector proteins. Instead, we found the compounds to exhibit dual‐functionality by also down‐regulating transcription of the entire chromosomal locus encoding the T3SS, further demonstrating their desirability and effectiveness.
Highlights
Antibiotic resistance is increasing among common bacterial pathogens and is considered a global threat by the World Health Organization
Anti-virulence (AV) compounds are a promising alternative to traditional antibiotics for fighting bacterial infections
The Type Three Secretion System (T3SS) is a well-studied and attractive AV target, given that it is widespread in more than 25 species of Gramnegative bacteria, including enterohemorrhagic E. coli (EHEC), and as it is essential for host colonization by many pathogens
Summary
Antibiotic resistance is increasing among common bacterial pathogens and is considered a global threat by the World Health Organization (http://www.who.int/en/). A key feature of this strategy is that ‘virulence-blocking’ mechanisms designed to target only the functionality of virulence factors carried by pathogens. This specificity helps avoid effects on the endogenous microflora and thereby exerts less selective pressure, reducing the development of resistance (Rasko and Sperandio, 2010; Beckham and Roe, 2014; Allen et al, 2014). The T3SS is a complex needle-like structure that penetrates the host cell membrane and functions as a conduit to translocate virulence effectors, intimately attach and creating a niche to allow the pathogen to survive (Cornelis, 2006; Bu€ttner, 2012)
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