Development of novel antibacterial agents through the design and synthesis of Aminoacyl tRNA Synthetase (AaRS) inhibitors

Antimicrobial resistance is a global public health issue which significantly threatens human life. There are approximately 50,000 deaths in the USA and Europe per year owing to antimicrobial resistance infections. This burden of resistance has increased resulting in an increase in morbidity and mortality in clinical and community setting. Thus, global collaborative action is needed for developing effective strategies to combat antimicrobial resistance. International and local approaches including antimicrobial surveillance, guidelines for treatment of bacterial infections, regulation of the availability of antibiotics, improving hand hygiene, understanding the mechanism of bacterial resistance and development of new antimicrobial agents have been advised. Aminoacyl tRNA synthetases are valuable targets for antibiotic development as they have a fundamental role at a cellular level during the translation process of the genetic code. Mupirocin (Bactroban ®) is an approved isoleucine tRNA synthetase inhibitor which is used for the treatment of methicillin resistant Staphylococcus aureus (MRSA). High and low level of mupirocin resistance has been demonstrated in most S. aureus isolates due to acquired plasmid-mediated mupA, which encodes a novel IleRS and mutation, respectively. Thus, the design of multitarget aminoacyl tRNA synthetases inhibitors could be an effective way to make significant reductions in the biological fitness of bacteria leading to a reduction in drug resistant microorganisms. Class IIb aminoacyl tRNA synthetases of which AspRS and AsnRS belong is a target of the project in Staphylococcus aureus and Enterococcus faecalis. A computational study of both enzymes in both microorganisms including homology modelling, validation techniques, molecular dynamics and docking of the natural substrates (aa-AMP) were used to be a platform for the design of dual site inhibitors containing a sulphamoyl linkage which mimic aa-AMP in both enzymes. Different series of AspRS/AsnRS inhibitors were designed to occupy both pockets of the target enzymes then synthesised after optimisation their synthetic routes. The minimum inhibitory concentration of compounds against a panel of microorganisms were evaluated compared with ciprofloxacin as the standard and one compound showed good inhibitory activity against Enterococcus faecalis (MIC = 2 μg/mL).