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New AntiBacterials with Inhibitory activity on Aminoacyl-tRNA Synthetases

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A new class of antibiotics

Antimicrobial resistance is a growing health issue worldwide with serious clinical consequences. Novel compounds are urgently needed to tackle resistant pathogens.

Health

In recent decades, there is a considerable decline in the number of new antibiotics that have been brought to the market. In addition, the ones under development belong to existing families of compounds against which resistance might have already been reported. There is a need for chemically-novel antibacterial agents that act on previously unexploited bacterial targets. Scientists on the EU-funded NABARSI (New antibacterials with inhibitory activity on aminoacyl-tRNA synthetases) project set out to identify inhibitors of aminoacyl-tRNA synthetases (aaRS), enzymes necessary to produce proteins within bacterial cells. To this end, they followed a cutting-edge drug discovery programme comprising novel computational screening technologies, synthetic methodologies as well as advanced mechanistic and in vitro studies. They studied multi-drug resistant (MDR) pathogenic bacteria including Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli. The drug design approach entailed both rational and in silico techniques that focused on chemical compounds with putative enzymatic inhibitory activity. A library was created of nearly eight million unique commercially available compounds. The inhibitory capacity of over 3 300 of these compounds was screened during NABARSI using innovative in vitro assays that enabled the measurement of bacterial aaRS enzyme activity inside human cells. Among the challenges encountered during the project was the identification of compounds that affected specific targets but did not inhibit bacterial growth and vice versa. Nonetheless, three new and potentially interesting aaRS antibiotics were discovered with a wide spectrum of activity against Gram-negative bacteria, including clinical isolates. Furthermore, patent applications have been filed for these structurally novel compounds. Considering the increased mortality and morbidity caused by drug resistant pathogens in hospitalised elderly and immune-suppressed patients, the NABARSI deliverables are of immense clinical importance. The further development and testing of these new antibiotics could improve EU healthcare systems and the life of thousands of patients every year.

Keywords

Antibiotics, antimicrobial resistance, NABARSI, inhibitor, aminoacyl-tRNA synthetase

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