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Banking on new antimicrobials: translational fidelity impairment

Final Report Summary - BONAFIDE (Banking on new antimicrobials: translational fidelity impairment.)

In our project we addressed a burning topic not only for infection biology but for public health – development of novel antibacterial drugs. Urgent need for new antibacterials is driven by the world-wide rising instances of diseases caused by multi-drug resistant bacteria. Conventional treatments of infections caused by multi-drug resistant pathogens are largely ineffective which leads to increased treatment costs, long-lasting illnesses and elevated death risk. In the absence of new efficient antibiotics the multi-drug resistant bacteria threaten to bring public health back into the pre-antibiotic era with frequent incidents of deadly epidemics. Novel antibacterials should serve as “the last line of defense” against the life-endangering infections. In spite of acknowledged pressing need recent successes in the new antibiotic discoveries have been extremely scarce.
With this project we contributed to the very first step of antibiotics development, namely, to the search of potential antibacterial targets. Such a target within a bacterial organism is a macromolecular entity essential for bacterial propagation and pathogenesis. Knowing a target is a pivotal point for the next step in development - screening of small molecules which can inhibit the target function in bacteria and therefore put infection under control. There have been many targets already identified and described for the existing antibiotics, which makes the further search even more challenging.
We have made comprehensive analysis of tRNA-modifying enzymes as underexplored targets within pathogenic Salmonella Typhimurium. Salmonella genus encloses a variety of bacterial species causing two major types of disease: gastrointestinal and systemic infections which together still cause thousands of deaths annually. Our choice to study significance of tRNA-modifying enzymes (tRMEs) as potential antibacterial targets has been directed with the following considerations. tRMEs as a class of molecules are present in all kingdoms of life including both bacteria as well as humans. These molecules serve efficiency and accuracy of fundamental function in any living organism – production of all proteins. Failure to produce proteins efficiently and accurately can cause disturbances in the intricately-regulated life functions of bacteria including reduction or complete loss of pathogenicity. Importance of protein production for pathogenicity has been previously exploited in numerous existing antibiotics which interfere with different parts of complex protein production machinery in bacteria and stall protein synthesis. In contrast, our approach investigated the impact of potential targets on bacterial virulence not due to their suggested involvement in total blocking of protein synthesis but via impeding its efficiency and accuracy. We have evaluated a large subset of tRMEs which have been implicated or indirectly alluded to fine-tuning of protein synthesis fidelity and efficiency for their significance in Salmonella pathogenicity. Using genetic mutagenesis approach and typhoid fever model in mice we have identified six tRMEs which are essential for Salmonella to cause systemic disease. These tRMEs are highly conserved among bacteria which is an indication on their potential to serve as novel broad-spectrum antibiotic targets. However, we do not want to underestimate a potential caveat involving partial amino acid similarity of these tRMEs to their human orthologs. This issue might complicate the next step in antibacterial development - search for small molecules specifically inhibiting bacterial tRMEs without side-effects involving human tRMEs. On the other hand there has been a positive example demonstrated by another group of scientists for the plausibility of bacteria-specific binding of small molecule to a tRME.
In addition we have contributed to unraveling the common details of mechanism how the function of these six tRMEs mediates development of virulence.
Altogether our results can serve as an initial step in antibacterial development based on several tRMEs as potential target candidates for novel antimicrobials.