Targeting Multiple Aminoacyl-tRNA Synthetases Overcomes the Resistance Liabilities Associated with Antibacterial Inhibitors Acting on a Single Such Enzyme

Abstract

bBacterial aminoacyl-tRNA synthetases (aaRSs) represent promising antibacterial drug targets. Unfortunately, the aaRS inhibitors that have to date reached clinical trials are subject to rapid resistance development through mutation, a phenomenon that limits their potential clinical utility. Here, we confirm the intuitively correct idea that simultaneous targeting of two different aaRS enzymes prevents the emergence of spontaneous bacterial resistance at high frequency, a finding that supports the development of multitargeted anti-aaRS therapies.T he aminoacyl-tRNA synthetase (aaRS) enzymes possess several features that render them promising prospects as broadspectrum antibacterial drug targets; they are essential for viability, are found in all bacterial pathogens, and are in many cases sufficiently structurally distinct from their eukaryotic counterparts to allow selective targeting (1, 2). Furthermore, chemical and clinical validation exists for these enzymes as useful targets for antibacterial chemotherapy (1). However, despite the potential promise of this family of targets, only a single aaRS inhibitor with a relatively limited indication has been approved for the management of bacterial infection. Mupirocin (MUP), an inhibitor of isoleucyltRNA synthetase, is a topical agent deployed for nasal decolonization of Staphylococcus aureus and for the treatment of superficial skin infection (3).Unfortunately, as with other antibacterial agents that act on a single enzyme target, aaRS inhibitors possess an intrinsic resistance liability (4). Mutants resistant to aaRS inhibitors are selected at a high frequency in bacterial populations (ϳ10 Ϫ7 ), typically as a result of point mutations within the gene encoding the drug target that lead to alteration of the latter in a manner that negatively impacts inhibitor binding (1). This liability, while manageable in the context of aaRS inhibitors such as MUP that are applied topically at concentrations sufficiently high to prevent or mitigate resistance, presents a problem for the development of aaRS inhibitors for systemic treatment of more serious bacterial disease. Indeed, GlaxoSmithKline halted phase II clinical trials of the leucyltRNA synthetase inhibitor GSK2251052 for the treatment of complicated urinary tract infections in adults following the emergence of mutants of Escherichia coli that were resistant to the drug in 3 of 14 patients within 2 days of administration (5).It has been proposed that the resistance liabilities associated with aaRS inhibitors could be overcome with an inhibitor capable of targeting two or more aaRS enzymes simultaneously (1, 2, 6); an equivalent effect could be achieved with a cocktail of two or more aaRS inhibitors delivered in combination. This proposal is supported by the multitarget hypothesis, which states that antibacterial agents for which resistance is not readily selected by mutation usually act on more than one cellular target (7). By targeting two or more aaRS enzymes simultaneously, a situation is created in which the likeliho...

Backbone Brackets and Arginine Tweezers delineate Class I and Class II aminoacyl tRNA synthetases

“…for angiogenesis [ 114 ]. Due to the highly individual characteristics of aaRS enzymes between organisms, it is possible to create precisely targeted antibiotics with minimal side effects [ 115 – 117 ].…”

Progress and challenges in aminoacyl-tRNA synthetase-based therapeutics

“…An alternative dual strategy that was tested featured the combined use of mupirocin and REP8839 JBC REVIEWS: Aminoacyl-tRNA synthetase as therapeutic targets as a topical antibacterial (39). This approach showed promise as a means to limit the emergence of resistant pathogens (see below) (87).…”

“…When bacterial cells are grown in the presence of single ARS inhibitors, resistant mutants arise at a relatively high frequency (ϳ10 Ϫ7 M), creating a serious potential liability for using these compounds. In a recent study, Randall et al (87) sought to estimate the frequency of resistant mutants when cells are treated with two distinct ARS inhibitors (i.e. mupirocin ϩ REP8839).…”

Backbone Brackets and Arginine Tweezers delineate Class I and Class II aminoacyl tRNA synthetases

“…Other authors suggested that both 114 classes evolved from unrelated ancestors and are of independent origin [23]. 115 Fig 2. The Rodin-Ohno hypothesis states that both aaRS classes descended from the opposite strands of a single gene.…”

“…for angiogenesis [114]. Due to the highly individual 543 characteristics of aaRS enzymes between organisms, it is possible to create precisely 544 targeted antibiotics with minimal side effects [115][116][117]. 545 Unfortunately, automatically mapped mutational data does not cover the Backbone 546 Brackets or Arginine Tweezers motif.…”