Antibacterial drug leads targeting isoprenoid biosynthesis

Wei Zhu, Yonghui Zhang, William Sinko, Mary E. Hensler, Joshua Olson, Katie J. Molohon, Steffen Lindert, Rong Cao, Kai Li, Ke Wang, Yang Wang, Yi Liang Liu, Anna Sankovsky, César Augusto F. De Oliveira, Douglas A. Mitchell, Victor Nizet, J. Andrew McCammon, Eric Oldfield

Research output: Contribution to journalArticle

Abstract

With the rise in resistance to antibiotics such as methicillin, there is a need for new drugs. We report here the discovery and X-ray crystallographic structures of 10 chemically diverse compounds (benzoic, diketo, and phosphonic acids, as well as a bisamidine and a bisamine) that inhibit bacterial undecaprenyl diphosphate synthase, an essential enzyme involved in cell wall biosynthesis. The inhibitors bind to one or more of the four undecaprenyl diphosphate synthase inhibitor binding sites identified previously, with the most active leads binding to site 4, outside the catalytic center. The most potent leads are active against Staphylococcus aureus [minimal inhibitory concentration (MIC)90 ∼0.25 μg/mL], and one potently synergizes with methicillin (fractional inhibitory concentration index = 0.25) and is protective in a mouse infection model. These results provide numerous leads for antibacterial development and open up the possibility of restoring sensitivity to drugs such as methicillin, using combination therapies.

Original languageEnglish (US)
Pages (from-to)123-128
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number1
DOIs
StatePublished - Jan 2 2013

Keywords

  • Drug discovery
  • Peptidoglycan
  • Protein structure
  • in silico high-throughput screening

ASJC Scopus subject areas

  • General

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  • Cite this

    Zhu, W., Zhang, Y., Sinko, W., Hensler, M. E., Olson, J., Molohon, K. J., Lindert, S., Cao, R., Li, K., Wang, K., Wang, Y., Liu, Y. L., Sankovsky, A., De Oliveira, C. A. F., Mitchell, D. A., Nizet, V., McCammon, J. A., & Oldfield, E. (2013). Antibacterial drug leads targeting isoprenoid biosynthesis. Proceedings of the National Academy of Sciences of the United States of America, 110(1), 123-128. https://doi.org/10.1073/pnas.1219899110