| Structural highlights
Publication Abstract from PubMed
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 Mg(2+)/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 Mg(2+) 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 MIC(90) values of ~250-500 ng/mL against S. aureus, 500 ng/mL against Bacillus anthracis, 4 mug/mL against Listeria monocytogenes and Enterococcus faecium, and 1 mug/mL against Streptococcus pyogenes M1, but very little activity against E. coli (DH5alpha, K12) or human cell lines.
HIV-1 Integrase Inhibitor-Inspired Antibacterials Targeting Isoprenoid Biosynthesis.,Zhang Y, Fu-Yang Lin, Li K, Zhu W, Liu YL, Cao R, Pang R, Lee E, Axelson J, Hensler M, Wang K, Molohon KJ, Wang Y, Mitchell DA, Nizet V, Oldfield E ACS Med Chem Lett. 2012 Apr 3;3(5):402-406. PMID:22662288[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhang Y, Fu-Yang Lin, Li K, Zhu W, Liu YL, Cao R, Pang R, Lee E, Axelson J, Hensler M, Wang K, Molohon KJ, Wang Y, Mitchell DA, Nizet V, Oldfield E. HIV-1 Integrase Inhibitor-Inspired Antibacterials Targeting Isoprenoid Biosynthesis. ACS Med Chem Lett. 2012 Apr 3;3(5):402-406. PMID:22662288 doi:10.1021/ml300038t
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