BONAFIDE

Banking on new antimicrobials: translational fidelity impairment

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 Obiettivo del progetto (Objective)

'Infectious diseases represent an incessant threat for the human population worldwide. The rapid evolution and flexible metabolism of bacterial pathogens have caused a staggering global rise in antibiotic resistance. Our project aims to contribute to the pressing need for discovery of new antibacterial targets. The project will combine the applicant`s expertise in molecular biology and biochemistry, together with the competence of the host lab in infection biology, bioinformatics and high-through-put methods, to evaluate potential targets for new antimicrobials development. Protein biosynthesis accuracy is an integral part of the living cell health. Errors during translation of genetic information into proteins may lead to nonfunctional and toxic product formation. We propose to evaluate frameshifting, the most severe type of translational inaccuracy, in a systematic and quantitative fashion as means to defeat bacterial pathogens. Our preliminary data show that it is possible to invoke avirulence by targeting frameshifting control in the pathogen Salmonella. To reach our objective, we have developed a fluorescence-based tool to monitor translational mistakes in vitro and in vivo using flow cytometry. We will collaborate with core facilities to use proteomics and gene expression profiling to decipher downstream effects of mistranslation. The results will be validated in the murine model of typhoid fever. These data will be used to create an in silico model for Salmonella that, fed by genomic information of other bacterial pathogens, could predict potential broad-spectrum drug targets. The academic benefit of the project involves promotion of an interdisciplinary approach and mutual exchange of state-of-the-art methodology between the host lab and the researcher. The researcher will enhance her individual competences as an independent investigator, master cutting-edge techniques, and strengthen her tutor skills within proposed out-reach activities.'

Introduzione (Teaser)

With imminent threat of an infection pandemic, European scientists have proposed a different way of fighting drug-resistant bacteria.

Descrizione progetto (Article)

Antibiotic resistance is a burning health issue and conventional treatments prove inefficient at tackling the problem. The synthesis of third-generation antibiotics has failed to successfully address antibiotic-resistant bacterial species, clearly indicating the urgent need for novel approaches.

In this context, scientists on the EU-funded 'Banking on new antimicrobials: Translational fidelity impairment' (BONAFIDE) project proposed to identify new targets on which to base the development of antibacterials. Given that antibacterial targets should be essential for bacterial propagation and pathogenesis, the consortium set out to evaluate the potential of tRNA-modifying enzymes (tRMEs). tRMEs participate in protein synthesis in all kingdoms of life, including bacteria and humans.

Although interfering with the protein production machinery has been explored before as an antimicrobial strategy, the BONAFIDE approach was designed to impact the fidelity and efficiency of protein synthesis. In this context, the consortium developed a fluorescence-based tool to monitor mistakes made during protein synthesis.

This helped them identify six tRMEs that are essential for salmonella pathogenicity. When these tRMEs were genetically modified, salmonella was unable to cause typhoid fever in a mouse model. Despite the novelty of the approach, there is a potential caveat associated with the evolutionary conservation of tRMEs across species. To avoid potential homology with human tRMEs and toxicity, researchers are looking for small molecules that are specific for bacterial tRMEs.

Alongside mechanistic information on the role of tRMEs in bacterial virulence, the BONAFIDE study provided evidence that is possible to invoke virulence by targeting the accuracy of pathogen protein synthesis. This opens up new avenues for the synthesis of novel antimicrobial compounds capable of addressing the immense problem of antibiotic resistance.