Display options
Cite
Zhang Y, Fu-Yang Lin, Li K, et al. HIV-1 Integrase Inhibitor-Inspired Antibacterials Targeting Isoprenoid Biosynthesis. ACS Med Chem Lett. 2012;3(5):402-406doi: 10.1021/ml300038t.
Zhang, Y., Fu-Yang Lin, Li, K., Zhu, W., Liu, Y. L., Cao, R., Pang, R., Lee, E., Axelson, J., Hensler, M., Wang, K., Molohon, K. J., Wang, Y., Mitchell, D. A., Nizet, V., & Oldfield, E. (2012). HIV-1 Integrase Inhibitor-Inspired Antibacterials Targeting Isoprenoid Biosynthesis. ACS medicinal chemistry letters, 3(5), 402-406. https://doi.org/10.1021/ml300038t
Zhang, Yonghui, et al. "HIV-1 Integrase Inhibitor-Inspired Antibacterials Targeting Isoprenoid Biosynthesis." ACS medicinal chemistry letters vol. 3,5 (2012): 402-406. doi: https://doi.org/10.1021/ml300038t
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 03;3(5):402-406. doi: 10.1021/ml300038t. PMID: 22662288; PMCID: PMC3363326.
Copy Download .nbib Format: NLM
Share it on

ACS Med Chem Lett. 2012 Apr 03;3(5):402-406. doi: 10.1021/ml300038t.

HIV-1 Integrase Inhibitor-Inspired Antibacterials Targeting Isoprenoid Biosynthesis.

ACS medicinal chemistry letters

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

Affiliations

  1. PrenylX Research Institute, Zhangjiagang, 215600, P.R. China.

PMID: 22662288 PMCID: PMC3363326 DOI: 10.1021/ml300038t

Abstract

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 μg/mL against Listeria monocytogenes and Enterococcus faecium, and 1 μg/mL against Streptococcus pyogenes M1, but very little activity against E. coli (DH5α, K12) or human cell lines.

References

  1. Pure Appl Chem. 2010;82(8):1585-1597 - PubMed
  2. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9150-4 - PubMed
  3. Science. 2000 Jan 28;287(5453):646-50 - PubMed
  4. Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):20057-62 - PubMed
  5. J Org Chem. 2007 May 11;72(10):3949-51 - PubMed
  6. J Med Chem. 2009 Feb 26;52(4):976-88 - PubMed
  7. Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1689-90 - PubMed
  8. J Med Chem. 2009 Aug 13;52(15):4869-82 - PubMed
  9. Proc Natl Acad Sci U S A. 2002 May 14;99(10):6661-6 - PubMed
  10. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7 - PubMed
  11. Nature. 2010 Mar 11;464(7286):232-6 - PubMed
  12. Mol Pharmacol. 2011 Oct;80(4):565-72 - PubMed
  13. Angew Chem Int Ed Engl. 2012 Jan 27;51(5):1124-37 - PubMed
  14. Nat Chem Biol. 2010 Sep;6(9):660-6 - PubMed
  15. J Med Chem. 2009 Jul 9;52(13):3869-80 - PubMed
  16. J Exp Med. 2005 Jul 18;202(2):209-15 - PubMed
  17. Acc Chem Res. 2010 Sep 21;43(9):1216-26 - PubMed
  18. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21337-42 - PubMed
  19. Bioorg Med Chem Lett. 2008 Mar 15;18(6):1840-4 - PubMed
  20. Bioorg Med Chem. 2009 Apr 1;17(7):2925-35 - PubMed
  21. Science. 2008 Mar 7;319(5868):1391-4 - PubMed
  22. J Med Chem. 2006 Dec 14;49(25):7331-41 - PubMed
  23. Biochemistry. 2010 Jun 29;49(25):5366-76 - PubMed
  24. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4806-9 - PubMed

Publication Types

Grant support