In search of antibacterial targets
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.
