Abstract
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.
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Acknowledgements
We wish to acknowledge the former leaders of the Pfizer Antibacterial Research Unit for their unfailing dedication and support during very challenging times. We would also like to acknowledge our former colleague, Zuoyu Xu, for development of the staging assay during his time at Pfizer.
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Montgomery, J., Smith, J., Tomaras, A. et al. Discovery and characterization of a novel class of pyrazolopyrimidinedione tRNA synthesis inhibitors. J Antibiot 68, 361–367 (2015). https://doi.org/10.1038/ja.2014.163
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DOI: https://doi.org/10.1038/ja.2014.163
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