Discovery and characterization of a novel class of pyrazolopyrimidinedione tRNA synthesis inhibitors.
Justin I Montgomery, James F Smith, Andrew P Tomaras, Richard Zaniewski, Craig J McPherson, Laura A McAllister, Sandra Hartman-Neumann, Joel T Arcari, Marykay Lescoe, Jemy Gutierrez, Ying Yuan, Chris Limberakis, Alita A Miller
A high-throughput phenotypic screen for novel antibacterial agents led to the discovery of a novel pyrazolopyrimidinedione, PPD-1, with preferential activity against methicillin-resistant Staphylococcus aureus (MRSA). Resistance mapping revealed the likely target of inhibition to be lysyl tRNA synthetase (LysRS). Preliminary structure-activity relationship (SAR) studies led to an analog, PPD-2, which gained Gram-negative antibacterial activity at the expense of MRSA activity and resistance to this compound mapped to prolyl tRNA synthetase (ProRS). These targets of inhibition were confirmed in vitro, with PPD-1 showing IC₅₀s of 21.7 and 35 μM in purified LysRS and ProRS enzyme assays, and PPD-2, 151 and 0.04 μM, respectively. The highly attractive chemical properties of these compounds combined with intriguing preliminary SAR suggest that further exploration of this compelling novel series is warranted.
