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 structureâactivity 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 35âμM in purified LysRS and ProRS enzyme assays, and PPD-2, 151 and 0.04âμM, 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.
对新型抗菌剂的高通量表型筛选发现了一种新型
吡唑并
嘧啶二酮 PPD-1,它对耐
甲氧西林金黄色葡萄球菌 (MRSA) 具有优先活性。抗性图谱揭示了可能的抑制目标是赖
氨酰 tRNA 合成酶 (LysRS)。初步的构效关系 (
SAR) 研究产生了一种类似物 PPD-2,它以牺牲 MRSA 活性和对映射到脯
氨酰 tRNA 合成酶 (ProRS) 的该化合物的抗性为代价获得了革兰氏阴性抗菌活性。这些抑制目标在体外得到了证实,PPD-1 在纯化的 LysRS 和 ProRS 酶测定中显示的 IC50 分别为 21.7 和 35-μM,PPD-2 分别为 151 和 0.04-μM。这些化合物极具吸引力的
化学性质与令人感兴趣的初步比吸收率相结合,表明有必要进一步探索这一引人注目的小说系列。