The polyketide natural product reveromycin A (RM-A) exhibits antifungal, anticancer, anti-bone metastasis, anti-periodontitis and anti-osteoporosis activities by selectively inhibiting eukaryotic cytoplasmic isoleucyl-tRNA synthetase (IleRS). Herein, a co-crystal structure suggests that the RM-A molecule occupies the substrate tRNAIle binding site of Saccharomyces cerevisiae IleRS (ScIleRS), by partially mimicking the binding of tRNAIle. RM-A binding is facilitated by the copurified intermediate product isoleucyl-adenylate (Ile-AMP). The binding assays confirm that RM-A competes with tRNAIle while binding synergistically with l-isoleucine or intermediate analogue Ile-AMS to the aminoacylation pocket of ScIleRS. This study highlights that the vast tRNA binding site of the Rossmann-fold catalytic domain of class I aminoacyl-tRNA synthetases could be targeted by a small molecule. This finding will inform future rational drug design.
Transition metals are indispensable nutrients for all cellular life and are frequently incorporated into metalloproteins to serve as essential cofactors. 1 The competition between pathogens and human cells for transition metals is an important component of the pathogenesis of infectious diseases, and hosts have developed a strategy known as "nutritional immunity" to restrict the pathogens from accessing essential transition metals to prevent microbial infection. 2 Bacteria have evolved various systems to subvert metal sequestration: elemental metal import, extracellular metal capture by metallophores, and metal acquisition from host metalloproteins, and these systems vary among species. [3][4] Metallophores are high-affinity
Aminoacyl-tRNA synthetases (aaRSs) are promising antimicrobial
targets due to their essential roles in protein translation, and expanding
their inhibitory mechanisms will provide new opportunities for drug
discovery. We report here that halofuginone (HF), an herb-derived
medicine, moderately inhibits prolyl-tRNA synthetases (ProRSs) from
various pathogenic bacteria. A cocrystal structure of Staphylococcus aureus ProRS (SaProRS)
with HF and an ATP analog was determined, which guided the design
of new HF analogs. Compound 3 potently inhibited SaProRS at IC50 = 0.18 μM and K
d = 30.3 nM and showed antibacterial activities with an
MIC of 1–4 μg/mL in vitro. The bacterial
drug resistance to 3 only developed at a rate similar
to or slower than those of clinically used antibiotics in
vitro. Our study indicates that the scaffold and ATP-aided
inhibitory mechanism of HF could apply to bacterial ProRS and also
provides a chemical validation for using bacterial ProRS as an antibacterial
target.
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