Figure 5: BN represents a new class of AARS inhibitor.

All aminoacyl-tRNA synthetases (AARSs) contain three pockets for binding its natural substrates (amino acid, ATP and tRNA-A76) to catalyse the two-step aminoacylation reaction. It involves the activation of amino acid by ATP to form an aminoacyl adenylate (AA-AMP), followed by a transfer of the aminoacyl-group from the high-energy intermediate AA-AMP to the 3′-OH of tRNA. Type Ia inhibitors including AA-AMS, Agrocin 84, mupirocin etc., mimic AA-AMP and occupy amino acid and ATP pockets (see also Table 1). The type Ib inhibitor halofuginone (HF) mimics prolyl-tRNA 3′-A76, and binds to proline and tRNA-A76 pockets on prolyl-tRNA synthetase (ProRS). The type Ic inhibitor AN2690 co-binds and traps tRNA in the leucyl-tRNA synthetase (LeuRS)-editing domain. The new (type II) inhibitor Borrelidin (BN) binds at a joint region of amino acid, ATP and tRNA pockets, as well as an extra induced-fit pocket in the active site cavity of ThrRS. As an 18-member macrolide, BN does not resemble the native substrates, but binds to the active site of ThrRS through an unseen geometrically fitting mechanism.