HIV-1 integrase inhibitor-inspired antibacterials targeting isoprenoid biosynthesis

Yonghui Zhang, Fu Yang Lin, Kai Li, Wei Zhu, Yi Liang Liu, Rong Cao, Ran Pang, Eunhae Lee, Jordan Axelson, Mary Hensler, Ke Wang, Katie J. Molohon, Yang Wang, Douglas A. Mitchell, Victor Nizet, Eric Oldfield

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)402-406
Number of pages5
JournalACS Medicinal Chemistry Letters
Issue number5
StatePublished - May 10 2012

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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