1370459-47-4Relevant academic research and scientific papers
HIV-1 integrase inhibitor-inspired antibacterials targeting isoprenoid biosynthesis
Zhang, Yonghui,Lin, Fu-Yang,Li, Kai,Zhu, Wei,Liu, Yi-Liang,Cao, Rong,Pang, Ran,Lee, Eunhae,Axelson, Jordan,Hensler, Mary,Wang, Ke,Molohon, Katie J.,Wang, Yang,Mitchell, Douglas A.,Nizet, Victor,Oldfield, Eric
supporting information; experimental part, p. 402 - 406 (2012/06/29)
We report the discovery of antibacterial leads, keto- and diketo-acids, targeting two prenyl transferases: undecaprenyl diphosphate synthase (UPPS) and dehydrosqualene synthase (CrtM). The leads were suggested by the observation that keto- and diketo-acids bind to the active site Mg2+/Asp domain in HIV-1 integrase, and similar domains are present in prenyl transferases. We report the X-ray crystallographic structures of one diketo-acid and one keto-acid bound to CrtM, which supports the Mg2+ binding hypothesis, together with the X-ray structure of one diketo-acid bound to UPPS. In all cases, the inhibitors bind to a farnesyl diphosphate substrate-binding site. Compound 45 had cell growth inhibition MIC90 values of ～250-500 ng/mL against Staphylococcus aureus, 500 ng/mL against Bacillus anthracis, 4 μg/mL against Listeria monocytogenes and Enterococcus faecium, and 1 μg/mL against Streptococcus pyogenes M1 but very little activity against Escherichia coli (DH5α, K12) or human cell lines.
